Некодирующие PНK, регулирующие p53 и c-Myc сигналинг | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Некодирующие PНK, регулирующие p53 и c-Myc сигналинг

Введение

Опухолевый супрессор p53 контролирует рост и геномную стабильность нормальных клеток путем либо инициирования остановки клеточного цикла, либо стимулирования апоптоза в ответ на ДНК повреждение или другие типы клеточного стресса [1, 2]. Важность p53 как опухолевого супрессора подчеркивается фактом, что p53 инактивируется больше чем в половине всех канцеров человека. p53 вовлечен в регуляцию различных клеточных процессов, включая клеточную пролиферацию, клеточное старение и клеточный метаболизм. Большинство даунстрим-эффекторов p53 опосредовано его интринсиговым характером как основного транскрипционного фактора. Точно так же важность c-Myc как ключегого онкогена подчеркивается фактом, что c-Myc активируется больше чем в половине канцеров человека [3].

Многие механизмы, вовлеченные в активации c-Myc во время карциногенеза, включают амплификацию, хромосомную перестройку и точковые мутации в кодирующей последовательности гена. c-Myc обладает мощной трансформирующей способностью для промотирирования карциногенеза [4]. Поэтому, не удивительно, что экспрессия c-Myc находится под жестким контролем в нормальных клетках [5]. Например, c-Myc является геном раннего ответа (immediate early gene), и его транскрипция контролируется на уровне инициирования ответа на ряд ростовых стимулов. Кроме того, c-Myc mRNA высоко нестабильна, и экспорт и трансляция c-Myc mRNA также жестко контролируются в клетке.  Кроме того c-Myc — непродолжительно живущий протеин, и его стабильность регулируется множественными E3 убиквитин-лигазами, среди которых SCF (SkpCullin-F-box)-Fbw7 (F-box and WD repeat domain-containing 7) наилучше охарактеризованная E3 убиквитин-лигаза для c-Myc [6]. После альтерации контрольных механизмов, регуляция c-Myc нарушается, и он инициирует возникновение и прогрессирование опухоли.

Некодирующие PНK, регулирующие p53 сигналинг

Вследствие своего мощного антипролиферативного эффекта, p53 действует под чрезвычайно жесткой регуляцией, включая стабильность mRNA, трансляцию протеина и посттрансляционные модификации в здоровых клетках. Самый известный негативный регулятор p53 — Mdm2, который является принципиальной E3 убиквитин-лигазой для p53 и таргетирует его для быстрой деградации через путь убиквитин-протеасомный путь [7]. В ответ на клеточный стресс p53 стабилизируется и связывается с консенснусным отвечающим элементом (РЕ p53) в промоторе генов-мишеней p53, ведя к их транскрипционной активации. Среди них p21 является известным регулятором клеточного цикла. В дополнение к протеин-кодирующим генам некодирующие PНK представляют новый класс генов-мишеней p53. Кроме того, некодирующие PНK способны регулировать функцию p53 и служить как p53 регуляторы [8]. Вследствие важности p53 в инициировании и развитии канцера, возможно, что p53-ассоциированные некодирующие PНK — критические игроки в регуляции карциногенеза путем контроля p53 сигналинга, и также эти некодирующие PНK могут быть как потенциальными диагностическими маркерами и терапевтическими мишенями для противоопухолевого лечения.

Длинные некодирующие РНK, регулирующие p53 сигналинг

lncRNA играют важную роль в регуляции различных клеточных процессов. Дисрегуляция lncRNA вовлечена во многие болезни человека, включая канцер [9]. lncRNA могут функционировать как онкогенные и опухоль-супрессорные гены. Некоторые lncRNA вовлечены в регуляцию экспрессии p53, тогда как некоторые другие являются p53 мишенями и прямыми эффекторами p53 сигналинга. Ради простоты p53-ассоциированные lncRNA классифицировали как “p53 эффекторы” и «p53 регуляторы» в этом обзоре.

Длинные некодирующие РНK как эффекторы p53 сигналинга

Десятки lncRNA являются bona fide транскрипционными мишенями p53. Здесь мы представляем несколько типичных примеров регулируемых p53 lncRNA, которые действуют как эффекторы p53 сигналинга в канцере.

LincRNA-p21

Из отвечающих на p53 lncRNA, lincRNA-p21 индуцируется в мышиных клетках, где p53 селективно активирован. LincRNA-p21 локализуется приблизительно на 15 кб выше CDKN1A гена (p21), расположенного на хромосоме 17 у мышей и хромосоме 6 у человека и служит репрессором p53 пути, поскольку нокаут lincRNA-p21 изменяет экспрессию сотен таргетируемых генов, которые в нормальных условиях репрессируются p53. LincRNA-p21 функционирует путем взаимодействия с hnRNP-K и необходима для p53-инициируемого  апоптоза. lincRNA-p21 влияет на p53 путь, преимущественно действуя в цис, для активации экспрессии соседнего к нему гена, CDKN1A (p21) [15]. Вместе, эти находки демонстрируют lincRNA-p21 как важный медиатор p53 активности.

Несмотря на небольшую гомологию последовательности, человеческая копия мышиной lincRNA-p21 идентифицирована и, видимо, даунрегулируется во множественных типах опухолей [16]. В отличие от lincRNA-p21 мыши, который преимущественно локализуется в ядре [13], lincRNA-p21 человека преимущественно локализуется в цитозоле [17, 18]. LincRNA-p21 человека способна взаимодействовать с РНК-связывающим протеином HuR, через который lincRNA-p21 регулирует mRNA трансляцию [17]. Кроме того, lincRNA-p21 человека является гипоксия-отвечающей lncRNA и незаменима для повышения ассоциированного с гипоксей гликолиза [18]. p53 — фактор блокирования перепрограммирования, и p53-регулируемая lincRNA-p21 предотвращает перепрограммирование соматической клетки, поддерживая метилирование H3K9me3 и CpG в промоторах генов плюрипотентности [19].

PANDA

PANDA (p21-associated ncRNA DNA damage activated) идентифицирована как p53-регулируемая lncRNA, которая вовлечена в прогрессирование клеточного цикла и апоптоз [20]. ПАНДА расположена на 5 кб выше от промотора CDKN1A гена. p53 может связываться с РЕ p53, расположенным между CDKN1A и PANDA дивергентными промоторами [20, 21]. В результате экспрессия PANDA индуцируется ДНК повреждением в p53-зависимой манере. После индукции PANDA взаимодействует и секвестрирует транскрипционный фактор NF-YA с ограничением экспрессии проапоптотических генов, таких как APAF1, BIK и FAS. Супрессия PANDA сильно сенсибилизирует фибробласты человека к ДНК повреждение-индуцированному апоптозу [20]. Эти находки показывают, что PANDA — даунстрим-эффектор p53 в ответ на ДНК повреждение с ингибированием апоптоза. Однако, поскольку PANDA-секвестрируемый NF-YA может контролировать экспрессию и проапоптотических, и антиапоптотических генов в зависимости от клеточного контекста, не удивительно, что PANDA также показывает антипролиферативную активность в дополнение к вышеупомянутой антиапоптотической функции. Например, низкая экспрессия PANDA ассоциированна с прогрессированием немелкоклеточной карциномы легкого (NSCLC). Даунрегуляция PANDA позволяет NF-YA повышенно регулировать экспрессию антиапоптотический ген Bcl2 и промотирирует выживание клеток [21]. В целом эти находки предлагают интригующую роль PANDA как p53 мишени в организовывании тонкого равновесия между апоптозом и выживанием клеток в ответ на различные клеточные стрессы.

Loc285194

Loc285194 — lnсRNА, расположенная в хромосоме 3q13.31. Этот локус имеет частые фокальные альтерации числа копий (CNAs) и потерю гетерозиготности (LOH) в первичных образцах остеосаркомы [22], показывая, что loc285194 является опухолевым супрессором. В поддержку этого даунрегуляция loc285194 найдена в нескольких типах канцера [23, 24]. Loc285194 — транскрипционная мишень p53 [23]. Эктопическая экспрессия loc285194 ингибирует рост опухолевых клеток и in vitro и in vivo. Механистически, loc285194 проявляет свою опухоль-супрессорную функцию, действуя молекулярной губкой для miR-211, которая, как было известно, промотирует рост клеток. Эти находки предполагают, что loc285194 — p53-регулируемый опухолевый супрессор.

TUG1

TUG1 (taurine upregulated gene 1) первоначально идентифицирован как важный регулятор дифференцирования сетчатки у мышей [25]. Совсем недавно TUG1 был характеризован как транскрипционная мишень p53 [26]. TUG1 контролирует экспрессию генов, действуя как молекулярные подпорки для задействования хроматин-модифицирующих комплексов PRC1 или PRC2 [27, 28], показывая на интригующую возможность, что p53 может регулировать экспрессию специфического набора протеин-кодирующих генов через TUG1. Функционально, TUG1 регулирует клеточную пролиферацию в нескольких типах опухолей. Даунрегуляция TUG1 ассоциирована с плохим прогнозом для немелкоклеточного рака легкого, тогда как в плоскоклеточной карциноме пищевода, апрегуляция TUG1 промотирирует клеточную пролиферацию [26, 29]. Это несоответствие может быть объяснено специфичностью ткани или гетерогенностью опухоли для lnсRNА (например, статус p53).

p53-ассоциированные eRNA

eRNAs — класс некодирующих PНK, транскрибированных с ДHК последовательности энхансерных регионов [30]. В геноме связывание p53 наблюдается преимущественно в пределах энхансерных регионов и у человека, и у мыши [31]. Вероятно, p53 может регулировать энхансерную активность. Способность p53 модулировать энхансерную активность обеспечивает дополнительный слой сложности к p53 сети. Интригующе, несколько eRNAs, включая DUSP4, PAPPA и IER5, экспрессируются в p53-зависимой манере. Такие p53-регулируемые eRNA необходимы для эффективного транскрипционного повышения взаимодействующих таргетируемых генов и индукции p53-зависимой остановки клеточного цикла [32]. Вместе, эти находки предполагают, что p53 способен регулировать экспрессию специфического набора таргетируемых генов через eRNA.

Длинные некодирующие РНK как регуляторы p53 сигналинга

Хотя экспрессия генов регулируется на транскрипционном и на посттранскрипционном уровнях и lncRNA способна к модуляции транскрипции генов, свидетельство lncRNA-опосредованной транскрипционной регуляции p53 отсутствует. Здесь обсуждается несколько lncRNA, которые регулируют экспрессию p53 на посттранскрипционном уровне.

MALAT1

MALAT1 (Metastasis-associated lung adenocarcinoma transcript 1) повышенно экспрессируется в нескольких типах канцера, включая раке легкого, молочной железы и толстого кишечника [33, 34]. Эктопическая экспрессия MALAT1 повышает клеточную пролиферацию in vitro и промотирирует формирование опухоли у nude мышей.

Evidence from MALAT1 knockout model reveals that MALAT1 promotes metastasis of lung cancer through regulating expression of metastasis-related genes [35]. These studies strongly suggest that MALAT1 possess an oncogenic activity. Of great interest, MALAT1 serves as a repressor of p53 [36]. Depletion of MALAT1 in human fibroblasts activates doublestranded DNA damage response resulting in the induction of p53 and its downstream target genes. Correlated with p53 activation, MALAT1-depleted human fibroblasts exhibit the phenotype of G1 cell cycle arrest [36]. However, it is still unclear that the observed defects in cell cycle progression are due to the deregulation of p53. Therefore, it would be interesting and important to determine whether MALAT1 exerts its oncogenic activity through regulating the p53 pathway in the future.

MEG3

As an imprinted gene, maternally expressed gene 3 (MEG3) has been found to be downregulated in various types of human cancers [34]. Ectopic expression of MEG3 markedly inhibits growth of human cancer cells [37]. These studies suggest that MEG3 functions as a tumor suppressor. Of note, MEG3 is able to active p53 and stimulate p53-mediated gene expression [38]. To induce p53 expression, MEG3 appears to act through an indirect mechanism by suppressing Mdm2 levels and attenuating the inhibitory effect of Mdm2 on p53. However, it is still unknown how MEG3 downregulates Mdm2 expression. Intriguingly, MEG3-stimulated p53 transcription is selective, since MEG3 enhances expression of growth differentiation factor 15 (GDF15) by promoting p53 binding to its promoter, whereas expression of other p53 targets, like p21, is unaffected [38]. Therefore, it would be interesting to investigate whether and how MEG3 directs p53 binding to its specific target gene promoters.

Wrap53

WD repeat containing, antisense to p53 (Wrap53) is a natural antisense transcript of p53 [39]. Wrap53 is located upstream of the p53 gene on the opposite strand. Wrap53 gene is transcribed as three different isoforms, a, β, and γ, but only the a form, containing a complementary sequence to the first exon of p53, is able to regulate p53 expression [39]. The other two isoforms β and γ lacking this sequence fail to affect p53 levels. Functionally, knockdown of Wrap53 abrogates p53 induction in response to DNA damage, whereas ectopic expression of Wrap53 potentiates p53-dependent apoptosis [39]. Since Wrap53 and p53 mRNAs are able to form an RNA-RNA duplex, it has been speculated that this RNA-RNA interaction is required to stabilize the p53 transcript. Interestingly, a recent study has shown that CCCTCbinding factor (CTCF) is able to physically interact with Wrap53 and thereafter affect p53 levels [40], reinforcing the important role of Wrap53 in the regulation of p53 expression.

ROR

Regulator of reprogramming (ROR) was originally identified as a promoting factor of somatic cell reprogramming via attenuating p53-dependent apoptosis [41]. Further studies have demonstrated that ROR plays a special role in the p53 signaling network, since ROR not only regulates p53 protein expression but ROR itself is also regulated by p53 [42]. ROR represses p53 translation through a direct interaction with heterogeneous nuclear ribonucleoprotein I (hnRNP I). A 28-base ROR sequence with hnRNP I-binding ability is essential and sufficient for p53 repression. Functionally, ROR inhibits p53-mediated cell cycle arrest and apoptosis. On the other side, p53 binds to the p53-responsive element (p53 RE) in the ROR promoter and activates ROR expression. These findings suggest an existence of a unique autoregulatory feedback loop between p53 and ROR, through which p53 expression is delicately controlled in response to various cellular stresses.

In summary, the detailed regulations for long noncoding RNA as either p53 effectors or regulators are far more complicated than we have anticipated, and the listed examples above are just one aspect of these multifaceted investigations. Examples listed in the contents above are outlined in Fig. 13.1.

miRNA, регулирующие p53 сигналинг

miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level [43]. Dysregulation of miRNAs has been linked to a variety of human diseases including cancer [44]. Over the last decade, a growing number of miRNAs have been involved in the regulation of p53 signaling pathway [45, 46]. These noncoding RNAs join the p53 network either as effectors or regulators. More interestingly, some of the p53-regulated miRNAs are involved in complex feedback loops, through which miRNAs either amplify or fine-tune p53 signaling in response to different cellular stresses.

the-long-and-short-non-coding-rnas-in-cancer-biology-13-1

Фиг. 13.1. Длинные некодирующие РНK, регулирующие p53 сигналинг

miRNA как эффекторы p53 сигналинга

Since miR-34 was identified as the first p53 target miRNA gene, more than dozens of p53-regulated miRNAs have been discovered. We here focus on the miRNAs that act as effectors of p53 signaling in cancer. miR-34 is able to induce p53-dependent apoptosis, cell cycle arrest, and senescence [47–52]. miR-34 acts to induce cell cycle arrest by suppressing expression of a batch of cell cycle-related factors, including E2F3, cyclin E2, CDK4/6, and c-Myc. In addition, miR-34 can promote apoptosis in response to p53 activation through inhibiting expression of a number of anti-apoptotic proteins, including Bcl2 and DcR3. Besides, miR-34 is also involved in the regulation of other cellular processes, such as cell metabolism, epithelial to mesenchymal transition (EMT), and angiogenesis, all of which are of central importance to cancer cell biology. For instance, miR-34 regulates metabolic processes such as glycolysis and lipid metabolism through targeting LDHA, Sirt1, ASCL1, and ASCL4 [53]. Given the strong tumor-suppressive ability of miR-34, it is not surprising that miR-34 is downregulated in various cancer types [47, 48]. However, in contrast to p53-deficient mice, miR-34 knockout mice do not display increased susceptibility to spontaneous, irradiation-induced, or c-Myc-initiated tumorigenesis [54], indicating that miR-34 alone is not sufficient to mediate the potent tumor-suppressive function of p53.

Other miRNAs acting as p53 effectors include miR-15a/16, miR-107, miR-205, miR-145, miR-192/215, and miR-200 family members. Soon after the discovery of miR-34, miR-192/215 were found to induce cell cycle arrest in response to p53 activation by targeting several G1 and G2 checkpoint proteins, including CDC7, Cul5, and LMNB2 [55]. miR205 was also shown to reduce cell cycle progression by targeting E2F1 in response to p53 activation [56].

As the p53 transcriptional target, miR-15a/16 has been implicated in targeting genes involved in various p53 signaling pathways, such as apoptosis, cell cycle progression, cell proliferation, migration, and invasion. miR-15a/16 deletion has been found in several tumor types, including non-small cell lung cancer and prostate cancer [57]. The miR-200 family members have been associated with p53-regulated signaling pathways and also play an important role in suppressing cancer metastasis through direct targeting of genes including ZEB1/2, SOX2, and VEGF [58, 59]. miR-107 contributes to the function of p53 in the regulation of angiogenesis and hypoxic signaling through the targeting of HIF-1β. miR-107 is also able to induce G1 cell cycle arrest through suppression of CDK6 and RBL2 expression. Functionally, ectopic expression of miR-107 inhibits both tumor growth and angiogenesis in mouse colon cancer models [60, 61]. p53 directly binds to the p53 RE in the miR-145 promoter and induces its expression. Upon induction, miR-145 targets and negatively regulates expression of several cell cycle regulators including c-Myc and CDK4/6 [62], thereby leading to the inhibition of tumor cell proliferation.

Interestingly, some miRNAs are transcriptionally suppressed rather than induced by p53. For instance, the miR-17-92 cluster can be transcriptionally repressed by p53 in response to hypoxia, sensitizing cells to hypoxia-induced apoptosis [63]. In addition to regulating miRNA expression transcriptionally, p53 can also control miRNA expression posttranscriptionally by modulating miRNA processing and maturation [64]. p53 has been shown to interact with the Drosha complex and promote the cleavage of pri-miRNAs to pre-miRNAs. It has also been reported to affect miRNA target gene selection via the regulation of the RNA-binding protein RBM38 [65]. Furthermore, although most p53-regulated miRNAs function as tumor suppressors, some potentially act as oncogenes. miR-194 is transcriptionally upregulated by p53 and is able to target thrombospondin-1, leading to increased tumor angiogenesis [66]. In addition, the anti-apoptotic miR-149* has been shown to suppress expression of GSK-3a in response to p53 activation, resulting in increased expression of Mcl-1 and consequent resistance of melanoma cells to apoptosis [67].

miRNA как регуляторы p53 сигналинга

In addition to being the p53 targets, miRNAs are able to regulate p53 expression. miRNAs contribute to the tight control of p53 by either directly interacting with the 3’-UTR of p53 mRNA or indirectly downregulating p53 regulators.

Those miRNAs that bind p53 directly and function in a p53-repressive manner include miR-125b, miR-504, miR-33, miR-1285, miR-30d, miR-25, and miR-380 [68]. Due to the strongly tumor-suppressive function of p53, these p53-repressive miRNAs may be clinically relevant oncogenes. For example, miR-125b negatively regulates p53 expression by binding to the 3’-UTR of p53, resulting in decreased apoptosis [69]. In contrast, knockdown of miR-125b increases p53 protein levels and induces apoptosis. miR-125b also targets many other genes involved in the p53 signaling pathway. By using a gainand/or loss-of-function screen for miR-125 targets, in humans, mice, and zebra fish, miR-125b has been found to directly control at least 20 genes in the p53 network. Among them are modulators of apoptosis, such as Puma, Igfbp3, and Bak, and also several cell cycle regulators, including Cdc25C and cyclin C [70]. In colorectal cancers, elevated expression of miR-125b is associated with increased tumor size and invasion and correlated with poor prognosis and decreased survival. Also, the miR-125b gene is inherently activated by a chromosomal translocation t(11;14) (q24;q32) in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Eu/miR-125b transgenic mice with miR-125b overexpression develop lethal B-cell malignancies with clonal proliferation [71]. These studies indicate miR125b as a potential oncogene. However, miR-125b has also been shown to function as a tumor suppressor in breast cancer [72], suggesting that miR-125b may exert its function in a context-dependent fashion.

miR-504, miR-33, and miR-1285 downregulate p53 levels through two seed match sequences in the 3’-UTR of p53 [73]. Ectopic expression of these miRNAs attenuates p53-mediated cell cycle arrest and apoptosis and promotes tumorigenesis in colon cancer models. miR-30d and miR-25 are also able to decrease p53 levels by directly binding to its 3’-UTR [74], leading to the impaired downstream effects of p53, such as senescence, apoptosis, and cell cycle arrest. It has been observed that miR-30d and miR-25 are upregulated in multiple myelomas, which exhibit a concomitant downregulation of p53 expression. Additionally, the miR-30d gene is amplified in more than 30% of multiple types of human solid tumors (n = 1283), and enhanced expression of miR-30d is associated significantly with poor clinical outcomes in ovarian cancer patients [75]. miR-380 is found to repress p53 levels via a conserved sequence in the p53 3’-UTR in neuroblastomas commonly harboring wild-type p53. Neuroblastomas with elevated miR-380 expression have showed decreased patient survival. miR-380 overexpression cooperates with H-Ras oncoprotein in transformation, blocks oncogene-induced senescence, and promotes tumor formation in mice [76]. Furthermore, in vivo delivery of a miR-380 antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. Intriguingly, a recent study has found hundreds of novel somatic mutations in the 3’-UTR of p53 from B-cell lymphoma patients, and the seed match binding sites of 8 out of 11 p53-targeting miRNAs are disrupted by these mutations [77]. Altogether, these studies demonstrate the physiological importance of miRNAs in suppressing p53 tumor-suppressive function.

In addition to abovementioned miRNAs that directly repress p53, a number of miRNAs have been discovered to activate p53 by directly repressing Mdm2, such as miR-192, miR-194, miR-605, miR-25, miR-32, miR-143, miR-145, miR-660, and miR-661 [68]. Almost all of these miRNAs are able to inhibit cancer cell proliferation via promoting p53-mediated apoptosis, senescence, and/or cell cycle arrest. Some of them are also capable of repressing the migration and invasion of cancer cells to inhibit cancer metastasis. Other than directly repressing Mdm2, miR-122 indirectly decreases Mdm2 activity via the downregulation of cyclin G1 and subsequent inhibition of the recruitment of the PP2A phosphatase to Mdm2, resulting in increased p53 levels and activity. In addition to suppressing Mdm2, several miRNAs can also target other p53 regulators, such as Sirt1 and HDAC1, and thus control p53 activity [45]. For instance, miR-34a and miR-449 have been shown to target Sirt1, leading to increased p53 acetylation and p53-induced apoptosis. Interestingly, some of the miRNAs that positively regulate p53 activity, such as miR-192, miR-194, miR-215, miR-605, miR143, and miR-145, are also the transcriptional targets of p53, indicating the existence of a positive feedback loop that amplifies the p53 response to cellular stress.

Петли обратной связи, вовлеченные в miRNA-регулируемый p53 сигналинг

It has long been accepted that p53 and Mdm2 form a negative feedback loop, where p53 positively regulates Mdm2 by activating its transcription and Mdm2 negatively regulates p53 by promoting its ubiquitination and degradation. This feedback regulation has been recognized as a key mechanism in determining the cellular outcome in response to p53 activation. Interestingly, the feedback regulation can also be achieved by some p53-regulated miRNAs, either positively or negatively [73]. For instance, p53-induced miRNAs miR-192, miR-194, and miR-215 directly inhibit Mdm2 expression and protect p53 from Mdm2-mediated degradation [78, 79]. The combined ectopic expression of these miRNAs greatly enhances the therapeutic effectiveness of Mdm2 inhibitor MI-219 to treat multiple myeloma [79]. These miRNAs have been found to be downregulated in several cancer types, such as colorectal cancer and renal cell carcinoma (RCC). Also, miR-215 expression correlates positively with survival of RCC patients. In agreement with the identification of Mdm2 as the direct target of miR-192, miR-194, and miR-215, specimens from RCC patients exhibit an inversely correlated expression of mdm2 and these three miRNAs [80]. A similar positive feedback loop has been recently described for miR-605, which is induced by p53 and is able to negatively regulate Mdm2 expression [81]. miR-143 and miR-145, which belong to the same cluster, have been found to directly target Mdm2, and both miRNAs are posttranscriptionally upregulated by p53. These two miRNAs are downregulated in head and neck squamous cell carcinoma, while Mdm2 is upregulated in these tumors [82].

Some p53-regulated miRNAs can also modulate p53 levels by controlling the p53 regulators other than Mdm2. For example, as a p53-inducible miRNA, miR-29 targets and inhibits the expression of Cdc42 and the p85a regulatory subunit of PI3K [83], both of which are p53 negative regulators. In addition, upon DNA damage, miR-29 induced transcriptionally by p53 can upregulate p53 expression by targeting Ppm1d phosphatase [84], which is a negative regulator of p53. An additional example of a positive feedback loop is the signaling pathway involving p53, miR-34a, and Sirt1 [85]. In response to cellular stress, p53 induces the expression of miR-34a, which in turn increases p53 acetylation by targeting Sirt1. The resultant increase in p53 activity amplifies p53-mediated tumor-suppressive signaling to accelerate apoptosis, senescence, and cell cycle arrest.

Unlike the positive feedback loops discussed above, there are a few examples of negative feedback loops between p53 and miRNA. For instance, in glioblastoma, miR-25 and miR-32 are downregulated by p53. These two miRNAs can directly target Mdm2. Downregulation of Mdm2 by these miRNAs leads to p53 accumulation with subsequent cell cycle arrest, cell proliferation inhibition, and impaired tumor formation [86].

More and more p53-regulated or to-be-regulated microRNAs are emerging as important players in various aspects of biological or pathological processes. The abovementioned microRNAs involved in p53 signaling are depicted in Fig. 13.2.

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Фиг. 13.2. miRNA, регулирующие p53 сигналинг

Некодирующие PНK, регулирующие cMyc сигналинг

Как основной транскрипционный фактор, c-Myc связан приблизительно с 10-15% генов в геноме [87]. c-Myc может функционировать как глобальный усилитель уже активных промоторов [88]. Модулируя экспрессию множества протеин-кодирующих генов, c-Myc регулирует различные клеточные процессы, включая рост и дифференцирование клеток, клеточный цикл, клеточный метаболизм и трансформацию клеток. Некодирующие PНK, особенно длинные некодирующие РНK и miRNA, играют критическую роль в регуляции пути c-Myc сигнального пути [89, 90]. Длинные некодирующие РНK и miRNA соединяют сеть c-Myc сеть как эффекторы или регуляторы. Учитывая сильный опухоль-промотирующий эффект c-Myc, эти некодирующие PНK могут быть критическими регуляторами c-Myc-инициированного карциногенеза. Кроме того эти c-Myc-ассоциированные некодирующие PНK могут быть потенциальными диагностическими маркерами и терапевтическими мишенями в канцере.

Длинные некодирующие РНK, регулирующие c-Myc сигналинг

Отчетливая связь между c-Myc и lncRNA наблюдается в большом наборе раковых образований. Многие из недавно идентифицированных lncRNA являются c-Myc downstream генами-мишенями [89]. Эти c-Myc-отвечающие c-myc lncRNA способны регулировать пролиферацию и инвазию раковых клеток [91]. Кроме того, некоторые lncRNA регулируют экспрессию и функцию c-Myc. Здесь мы обсудим функциональную роль c-Myc-lncRNA сети в карциногенезе.

Длинные некодирующие РНK как эффекторы c-Myc сигналинга

Сегодня идентифицировано большое число lncRNA как прямых c-Myc downstream мишеней [92]. Некоторые из этих lncRNA являются онкогенными молекулами. Здесь обсуждается функциональная роль нескольких lncRNA как эффекторов в опосредовании c-Myc-инициированного карциногенеза.

H19

Ген H19, расположенный в локусе H19/инсулин-подобного фактора роста 2 (IGF2), подвергается геномному импринтингу, который ведет к отличительной аллельной экспрессии H19 от материнской аллели и IGF2 от родительской аллели [93]. Аберрантная экспрессия H19 связана с разнообразными канцерами человека. Хотя H19 был первоначально описан как опухолевый супрессор, более свежие изучения предлагают H19 в качестве онкогена, поскольку H19 реактивируется в различных канцерах человека, включая рак молочной железы, легкого и шейки матки [34].

c-Myc индуцирует H19 экспрессию через связывание с H19 промотором [94]. Нокаут H19 значительно уменьшает клоногенность и фиксация-независимый рост клеток рака легкого и молочной железы. Кроме того c-Myc и H19 экспрессия показывают сильную позитивную корреляцию в первичных карциномах молочной железы и легкого [94]. Эти находки показывают, что c-Myc-индуцированный H19 важен для регуляции карциногенеза.

CCAT1

CCAT1 (Colorectal Cancer-Associated Transcript 1) — высоко эффективный биомаркер для CRC, и его апрегуляция наблюдается во всех стадиях CRC [95]. CCAT1 также повышенно регулируется и в других типах канцера, таких как карцинома желудка. Экспрессия c-Myc и CCAT1 показывает сильную ассоциацию в карциноме желудка [96]. c-Myc способен повышать экспрессию CCAT1, прямо связываясь с его промоторным регионом. В клетках рака желудка и рака толстого кишечника, гиперэкспрессия CCAT1 промотирирует клеточную пролиферацию и инвазию [96, 97]. Эти изучения предполагают, что c-Myc-активированный c-myc CCAT1 может способствовать формированию рака желудка и рака толстого кишечника.

MINCR

MINCR (Myc-Induced Long Noncoding RNA) недавно идентифицирована как c-Myc-индуцибeльная lncRNA [98]. MINCR показывает сильную корреляцию с c-Myc экспрессией в канцере. Нокаут MINCR уменьшает связывание c-Myc с промоторами селективных генов клеточного цикла, ведя к редуцированной экспрессии этих генов и результирующему ингибированию клеточной пролиферации.

BCYRN1

BCYRN1 (Brain Cytoplasmic RNA 1) первоначально идентифицирована как некодирующая PНK с длиной 200-nt (brain cytoplasmic 200, lncRNA-BC200), которая селективно экспрессируется в нервной системе приматов. Она повышенно экспрессируется в канцере молочной железы, шейки матки, пищевода, легкого, яичника, околоушной железы, языка и немелкоклеточном раке легкого [99,100]. c-Myc связывается с промоторным регионом BCYRN1 гена и повышает BCYRN1 экспрессию. Функционально, BCYRN1 необходима для c-Myc-промотирируемой клеточной миграции и инвазии, показывая что c-Myc-активированная BCYRN1 может быть онкогенной молекулой.

Длинные некодирующие РНK как регуляторы c-Myc сигналинга

Emerging evidence suggests that lncRNAs are able to regulate gene expression at different levels, such as chromatin remodeling, transcription, and posttranscriptional processing. Several lncRNAs have recently been shown to regulate c-Myc expression at multiple levels, thus acting as regulators of c-Myc signaling in cancer.

CCAT1-L

Like the abovementioned CCAT1, its alternative splicing isoform CCAT1-L is also found to be significantly upregulated in CRC tissue samples compared to their normal tissue samples. In addition, CCAT1-L is expressed in several CRC-derived cell lines but not in non-CRC cell lines. The CCAT1-L transcript is encoded within the enhancer region 515 kb upstream of the c-Myc gene. Interestingly, CCAT1-L is able to promote c-Myc transcription via establishing an intra-chromosome looping between the Myc promoter and its upstream enhancer element [101]. Knockdown of CCAT1-L reduces long-distance interaction between the c-Myc promoter and its enhancers, resulting in the reduction of c-Myc transcription, suggesting that CCAT1-L functions in cis to regulate c-Myc expression.

GHET1

Gastric carcinoma high expressed transcript 1 (GHET1) was originally identified as a lncRNA that was overexpressed in gastric carcinoma [102]. It was later found to be also upregulated in bladder cancer [103]. Overexpression of GHET1 is closely related to increased tumor size, enhanced tumor invasion, and poor survival in patients. Ectopic expression of GHET1 promotes cancer cell proliferation, whereas knockdown of GHET1 has the opposite effect. Mechanistically, GHET1 enhances the interaction between c-Myc mRNA and insulin-like growth factor 2 mRNAbinding protein 1 (IGF2BP1), thereby resulting in the increased stability of c-Myc mRNA and expression. Knockdown of c-Myc suppresses the ability of GHET1 to promote cancer cell proliferation. Besides, the expression of GHET1 and c-Myc is strongly correlated in gastric carcinoma tissues. Altogether, these findings suggest that GHET1 promotes tumorigenesis via increasing c-Myc mRNA stability.

GAS5

Growth arrest-specific 5 (GAS5) has been implicated in the regulation of multiple cellular processes, including apoptosis, cell cycle arrest, and cell proliferation [104]. Low expression of GAS5 is associated with a poor prognosis in head and neck squamous cell carcinoma. Also, GAS5 is considered as a potential diagnostic marker and therapeutic target for non-small cell lung cancer. Molecular mechanisms of GAS5 action include riborepression of certain steroid hormone receptors and sequestration of several miRNAs [104]. A recent study has showed that GAS5 binds to c-Myc mRNA and suppresses c-Myc translation via cooperating with the eukaryotic translation initiation factor 4E (eIF4E) [105], suggesting that GAS5 may exert its tumor-suppressive function through repressing c-Myc expression.

PCAT-1

Prostate cancer-associated ncRNA transcript 1 (PCAT-1) has been shown to be upregulated in prostate cancer. In addition, PCAT-1 is implicated as a prognostic biomarker for colorectal cancer metastasis and poor patient survival [106, 107]. Ectopic expression of PCAT-1 promotes prostate cell proliferation. This PCAT-1enhanced proliferation is dependent on c-Myc, as knockdown of c-Myc reverses the effect of PCAT-1 on cell proliferation. Mechanistically, PCAT-1 posttranscriptionally regulates c-Myc expression by abrogating the downregulation of c-Myc by miR-34a [108]. These findings indicate an oncogenic role of PCAT-1 in prostate cancer proliferation through c-Myc.

PVT1

Plasmacytoma variant translocation 1 (PVT1) is transcribed from approximately 100–500 kb downstream of the c-Myc gene locus within the chromosomal region 8q24.21. It has been shown that overexpression of PVT1 is significantly associated with increased metastasis and poor prognosis in many cancers, including breast, colon, gastric, and ovarian cancers [109, 110]. By analyzing available databases, it has been found that >97% of tumors with amplified 8q24 region show a co-gain of c-Myc and PVT1. This PVT1 and c-Myc protein co-amplification is also confirmed in a panel of eight human primary tumors [111]. Interestingly, knockdown of PVT1 reduces c-Myc protein levels, leading to inhibited cell proliferation and impaired tumor formation. Mechanistically, PVT1 positively regulates c-Myc protein expression via reducing its phosphorylation at threonine 58 (Thr58) and protecting it from proteasome-dependent degradation [111]. These findings suggest that PVT1 is an important regulator of tumorigenesis by controlling c-Myc protein stability.

PCGEM

Prostate cancer gene expression marker 1 (PCGEM) is a prostate tissue-specific lncRNA and highly associated with prostate cancer [112]. Overexpression of PCGEM has been found in over 80% of patient prostate tumor specimens. Ectopic expression of PCGEM is able to promote cell proliferation, increase colony formation, and confer resistance to doxorubicin-induced apoptosis [113]. These findings highly suggest the oncogenic role of PCGEM in prostate cancer. Interestingly, it has been recently shown that PCGEM1 functions as a critical regulator of cell metabolism that facilitates the biosynthesis of cellular building materials, thus providing growth advantages for cancer cells [114]. PCGEM1 regulates metabolic reprogramming predominantly by enhancing activation of c-Myc and controlling c-Mycdependent expression of multiple genes involved in the key metabolic pathways. The PCGEM-mediated c-Myc activation involves the direct binding of PCGEM to c-Myc that facilitates the recruitment of c-Myc to the chromatin target sites [114]. Altogether, these findings uncover PCGEM as a critical regulator of metabolic reprogramming of prostate cancer cells by being a coactivator of c-Myc.

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Фиг. 13.3. Длинные некодирующие РНK, регулирующие c-Myc сигналинг

In conclusion, long noncoding RNAs involved in regulating c-Myc signaling are emerging as novel strategies in studying gene regulation which will benefit both basic and clinical investigations. The pathways utilized by several long noncoding RNAs are briefly sketched in Fig. 13.3.

miRNA, регулирующие c-Myc сигналинг

miRNAs have been widely implicated as components of both tumor-suppressive and oncogenic pathways. In particular, miRNAs have been linked to the c-Myc signaling pathway. c-Myc is able to regulate a number of miRNAs, which contribute to all key c-Myc-driven phenotypes, including apoptosis, cell cycle progression, metabolism, angiogenesis, and metastasis [90, 115]. Moreover, the expression of c-Myc itself is subjected to the regulation by miRNAs, leading to sustained c-Myc activity and the corresponding c-Myc downstream pathway. Here, we will discuss how miRNAs mediate and regulate c-Myc functions in cancer.

miRNA как эффекторы c-Myc сигналинга

c-Myc can either induce or repress miRNA expression. miRNAs that are induced by c-Myc include miR-17-92, miR-378, and miR-22. miR-17-92 is identified as the first c-Myc-induced miRNA cluster [116, 117]. The miR-17-92 cluster encodes six distinct miRNAs, including miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1. The c-Myc-stimulated miR-17-92 cluster has been shown to mediate c-Myc-regulated cellular processes, such as cell cycle, apoptosis, and metabolism. For instance, miR-17 and miR-20a are able to directly target p21 and inhibit its expression, leading to accelerated cell cycle progression. Besides, the E2F1 family of transcription factors that regulate cell cycle progression is also targeted by miR17 and miR-20a. The miR-17-92 cluster also inhibits apoptosis by targeting Bim, PTEN, PP2A, and AMPK [118], all of which are positive regulator of apoptosis. Furthermore, by suppressing expression of PP2A and AMPK, miR-19a/b stimulates the Akt and mTOR signaling and thereafter promotes aerobic glycolysis [119].

In agreement with its oncogenic activity, the miR-17-92 cluster is frequently activated in multiple solid tumors and B-cell lymphomas. Transgenic expression of the miR-17-92 cluster, under the control of the IgH promoter, results in B lymphoma development in mice [120]. In addition, conditional knockout of miR17-92 in c-Myc-initiated lymphomas reduces their tumorigenicity. Furthermore, ectopic expression of the miR-17-92 cluster in PTEN deletion-induced retinoblastomas, as well as in granule neuron progenitors and colorectal colonocytes, greatly enhances tumorigenesis [121–123]. Altogether, these findings suggest that the miR17-92 cluster represents a bona fide oncogene and an important mediator of c-Mycdriven tumorigenesis.

Another c-Myc-induced miRNA, miR-378, has been recently shown to act as an oncogenic miRNA [124]. miR-378 is able to cooperate with activated Ras or HER2 to promote cellular transformation. miR-378 exerts this oncogenic effect by targeting and inhibiting the antiproliferative BTG family member TOB2. In addition, miR-22 is also an oncogenic c-Myc-induced miRNA. miR-22 triggers epithelialmesenchymal transition (EMT), enhances invasiveness, and promotes metastasis in mouse xenografts. It also exerts its metastatic potential by silencing miR-200 gene through direct inhibition of methylcytosine dioxygenase ten-eleven translocation (TET) proteins [125].

In addition to activating miRNA expression, c-Myc is also able to repress the expression of a number of miRNAs. These c-Myc-repressed miRNAs include let7, miR-23a/b, miR-15a/16, miR-34, and miR-26. Let-7 is repressed by c-Myc in an unconventional fashion. c-Myc stimulates the expression of Lin28 and Lin28b, which bind the let-7 pre-miRNA stem loop, and thereby prevents processing by Drosha and Dicer [126]. Inhibition of let-7 leads to increased proliferation, whereas overexpression of let-7 results in cell cycle arrest. This let-7-regulated phenotype involves in the direct suppression of high-mobility group protein A2 (HMGA2) and several positive cell cycle regulators, such as CDK6 and CDC25A [127, 128]. In addition to let-7, miR-23a and miR-23b are also repressed by c-Myc. By repressing miR-23a and miR-23b, c-Myc increases the expression of GLS-1, a key enzyme responsible for the conversion of glutamine to glutamate, which serves as a substrate in the TCA cycle for the energy production [129], thereby leading to accelerated cancer cell proliferation.

The miR-15a/16 cluster is located in an intronic region of the DLEU2 gene, which is directly repressed by c-Myc [130]. Deregulation of these miRNAs has been implicated in multiple human cancers. Loss of miR-15a/16 expression is sufficient to develop chronic lymphatic leukemia (CLL) in mice [131]. By directly targeting several oncogenic factors, such as Bcl2 and cyclin D1, miR-15a/16 induces apoptosis and cell cycle arrest, thereby exerting its tumor-suppressive function [132, 133].

As mentioned earlier, miRNA-34 is positively regulated by p53 and is important for the tumor-suppressive function of p53. It has been also shown that miR-34 is repressed by c-Myc [134]. Therefore, the regulation of miR-34 may serve as an important platform of the antagonism between c-Myc and p53. By repressing miR34 expression, c-Myc antagonizes several functions ascribed to miR-34, such as inhibition of cell cycle progression and induction of apoptosis and senescence, thereby contributing to tumor initiation and progression [115]. Interestingly, in certain contexts, miR-34 shows an oncogenic activity instead of tumor-suppressive function. For example, in B lymphoid cells with enhanced c-Myc expression, ectopic expression of miR-34, which does not directly target p53, significantly decreases p53 protein levels [135]. This effect is mediated by downregulation of c-Myc, which stimulates p53 expression via the ARF-Mdm2 axis. As a result, in cells with the intact c-Myc-ARF-Mdm2-p53 pathway, miR-34 is able to inhibit p53-dependent apoptosis. Thus, in certain tumors with upregulated c-Myc expression, miR-34a may serve as a potential therapeutic target.

miR-26 is another c-Myc-repressed miRNA. Ectopic expression of miR-26 has been shown to induce cell cycle arrest in hepatocellular carcinoma cells (HCC) by directly targeting repression of several positive cell cycle regulators, such as CCND2 and CCNE2 [136]. These results suggest that c-Myc may contribute to HCC through repressing miR-26 expression. In support of this, restoration of miR-26 expression shows the therapeutic efficacy in a c-Myc-driven mouse model of HCC [137]. This efficacy is likely due to the cell cycle arrest caused by miR-26. Besides repressing miR-26, c-Myc may also promote HCC tumorigenesis through a miRNA-mediated positive feedback loop comprising of miR-148a, miR-363, and the ubiquitinspecific protease 28 (Usp28) [138]. c-Myc is able to directly bind to the promoters of miR-148a and miR-363 and suppress their expression. miR-148a directly targets c-Myc and inhibits its expression, while miR-363 destabilizes c-Myc protein via targeting and inhibiting Usp28. As a result, ectopic expression of miR-148a and miR-363 promotes HCC tumorigenesis, whereas inhibition of these miRNAs has an opposite effect. Taken together, these studies demonstrate miRNA as an important class of noncoding RNA that is involved in the regulation of c-Myc-driven tumorigenesis.

miRNA как регуляторы c-Myc сигналинга

The interaction of c-Myc and miRNAs is mutual, as a number of miRNAs have been described that regulate c-Myc expression. For example, miR-33b is a negative regulator of c-Myc through direct binding to the 3’-UTR of c-Myc mRNA [139]. Restored expression of miR-33b in a cell line without endogenous miR-33b decreases c-Myc levels, reduces anchorage-independent growth, and attenuates tumor formation in nude mice. miR-375 is able to indirectly repress c-Myc expression by targeting the cancerous inhibitor of PP2A (CIP2A) [140], a guardian of c-Myc protein. As expected, ectopic expression of miR-375 in oral cancer cells decreases c-Myc protein levels and reduces cell proliferation, colony formation, migration, and invasion.

As discussed above, p53-induced miR-34 represses c-Myc expression. Several other p53-induced miRNAs can also target c-Myc. For instance, as a p53-induced miRNA, miR-145 is able to directly bind to the 3’-UTR of c-Myc mRNA [62]. Ectopic expression of miR-145 silences the expression of c-Myc, whereas knockdown of miR-145 enhances its expression. Furthermore, miR-145-mediated c-Myc silencing accounts at least in part for the miR-145-mediated tumor growth inhibition.

As a c-Myc-repressed miRNA, let-7 has been shown to directly repress c-Myc [141]. Ectopic expression of let-7 reduces both mRNA and protein levels of c-Myc, thus reverting c-Myc-induced growth in Burkitt lymphoma cells. Interestingly, two different miRNAs, miR-196b and miR-184, are able to concomitantly suppress c-Myc and Bcl2 expression, leading to the inhibition of cell proliferation and survival [142, 143]. Similarly, overexpression of miR-449c inhibits tumor cell migration and invasion via direct targeting of c-Myc. miR-449 also achieves its tumor-suppressive function by targeting other factors such as E2F1.

Interestingly, miR-24, which is upregulated during terminal differentiation of multiple lines, can repress c-Myc expression via “seedless” 3’-UTR microRNA recognition element [144]. miR-135b targets and inhibits c-Myc expression in osteosarcoma cells [145]. Inhibition of miR-135b accelerates cell proliferation, migration, and invasion, whereas forced expression of miR-135b has the opposite effect. Moreover, ectopic expression of c-Myc recovers miR-135b-inhibited cell proliferation and invasion, suggesting that miR-135b may function as a tumor suppressor via targeting c-Myc. It has been recently shown that ribosomal protein L11 regulates c-Myc mRNA turnover [146]. The unique protein-RNA complex formed by L11, Ago2, RISC, and miR-24 binds to the 3’-UTR of c-Myc mRNA and promotes its degradation. Altogether, these findings suggest that miRNA represents another important layer of the complexity of c-Myc regulation.

More microRNAs involved in c-Myc signaling still await to be characterized, and we have every reason to believe that by unveiling the underlying mechanism of those microRNAs in regulating c-Myc signaling, it will help us to gain a better understanding in noncoding RNA research field. Regulation of microRNAs in c-Myc signaling in this chapter can be seen in Fig. 13.4.

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Fig. 13.4. miRNAs regulating c-Myc signaling

Заключение

With the advancement of high-throughput sequencing technologies, it has been recognized that the number of noncoding genes largely exceeds that of protein-coding genes. This has led to one of the most significant shifts in our understandings of gene regulatory networks. Given that RNA is an evolutionary predecessor of proteins, noncoding RNA may represent an ancient mechanism by which gene expression is finely controlled. Here, we reviewed recent findings regarding the critical role of noncoding RNAs, especially miRNAs and lncRNAs, in regulating p53 and c-Myc signaling. Given the importance of p53 and c-Myc in the regulation of tumorigenesis, it is not surprising that some p53and c-Myc-related noncoding RNAs are involved in tumor initiation and/or progression, and also these noncoding RNAs may represent as potential cancer biomarkers and targets for cancer treatment. However, there are still some critical issues that remain to be addressed. For example, by acting as master transcription factors, both p53 and c-Myc are able to regulate a variety of noncoding RNA target gene expressions. Also, p53 and c-Myc signaling are subjected to the tight regulation by noncoding RNAs. It remains unclear how these complex noncoding RNA networks are integrated into a mechanical system for regulating p53 and c-Myc functions in cancer. In addition, although dysregulation of several p53and c-Myc-regulated noncoding RNAs has been implicated in tumorigenesis, the underlying mechanisms are largely unknown. Nevertheless, we believe that the noncoding RNA field is a rich landscape waiting to be further unveiled and functional exploration of noncoding RNA world will open unexpected possibilities, not only for biological but also for translational research.

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