BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

MITF is the master lineage regulator of melanocyte development and survival. It serves as the transcription factor for differentiation and pigmentation genes such as TYR, tyrosinase-related protein 1 (TYRP1), dopachrome tautomerase (DCT), melanoma antigen recognized by T-cells 1 (MART1, also known as gp100), and premelanosome protein (PMEL17, also known as SILV). Although MITF is essential for melanocyte differentiation, it can alternatively promote malignant behavior in some melanomas. The most common genetic alteration of MITF is amplification, which occurs in 15–20% of melanomas with a higher prevalence among metastatic melanomas [78]. MITF amplification is thought to usually occur as a late event in melanoma progression and was associated with poorer 5 year survival in the prevemurafenib and ipilimumab era [79]. Many melanomas continue to depend on MITF expression for survival, and suppression of MITF in vitro is lethal to most melanoma cell lines [80, 81].

The transcriptional targets of MITF that mediate its oncogenic activity as distinct from its regulation of pigmentation and differentiation are not fully characterized. However, MITF is known to enhance expression of genes involved in cell cycle progression, cell proliferation, and cell survival. For example, MITF is a transcription factor for cell cycle kinase CDK2 [81], CDK inhibitors p16INK4a [82] and p21 [83], and anti-apoptotic mitochondrial membrane protein B-cell lymphoma 2 (BCL-2) [84] as well as its related family member BCL2A1 [85]. In melanomas with elevated MITF activity, increased expression of these MITF targets likely contributes to growth, invasion, and survival of melanoma cells.

MITF is known to cooperate with BRAF in melanoma transformation in vitro [78] and in vivo [86]. MAPK pathway activation, which is found in the majority of melanomas, results in MITF phosphorylation at Ser73 by ERK2 [87]. Phosphorylation at Ser73 affects MITF regulation in two ways: enhanced recruitment of p300, an MITF transcriptional coactivator and histone acetyltransferase, and increased ubiquitination of MITF [88, 89]. Because Ser73 phosphorylation ultimately accelerates proteasomal degradation of MITF, MAPK signaling in melanomas can reduce expression of many MITF targets. BRAF inhibitors may enhance immunotherapy by stabilizing MITF and upregulating transcription of targets like MART1 and other antigens that are recognized by the immune response to melanoma [90].

Other post-translational modifications of MITF include phosphorylation by ribosomal S6 kinase (RSK), glycogen synthase kinase-3β (GSK-3), and p38 and sumoylation by protein inhibitor of the activated STAT3 (PIAS3) [91–94]. MITF is also a substrate for proteolytic degradation by caspase 3 [95]. Protein kinase C interacting protein 1 and PIAS3, which preferentially binds Ser73-phosphorylated MITF, inhibit MITF binding to DNA [14, 96–98]. Sumoylation of MITF reduces transcription of a subset of MITF targets whose promoters contain multiple MITF binding sites [99, 100]. In light of this observation and the complexity of MITF regulation, it is tempting to speculate that post-translational modifications determine MITF target gene specificity in response to cell context. By such mechanisms, MITF may be able to switch between its two recognized functions of regulating melanocytic differentiation/pigmentation and modulating survival/proliferation effects capable of producing an oncogenic transcriptional program in melanoma.

Germline loss-of-function mutation of MITF in humans causes Waardenburg syndrome type IIA, an autosomal dominant inherited condition characterized by lack of melanocytes in the eye, forelock, and inner ear [101]. Melanocyte deficiencies in individuals with Waardenburg syndrome result in deafness, white forelock (unpigmented hair in the midline), and eye color variability [102]. In contrast, increased numbers of nevi and darker eye colors are associated with the gain-of-function mutation conferred by a germline missense mutation in codon 318 of MITF. As previously discussed, this mutation abrogates a sumoylation site, resulting in altered transcription of some MITF targets and elevated melanoma susceptibility [12, 13] (Fig. 2.2).

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