MITF in melanoma: mechanisms behind its expression and activity

Abstract

MITF (microphthalmia-associated transcription factor) represents a melanocytic lineage-specific transcription factor whose role is profoundly extended in malignant melanoma. Over the last few years, the function of MITF has been tightly connected to plasticity of melanoma cells. MITF participates in executing diverse melanoma phenotypes defined by distinct gene expression profiles. Mutation-dependent alterations in MITF expression and activity have been found in a relatively small subset of melanomas. MITF activity is rather modulated by its upstream activators and suppressors operating on transcriptional, post-transcriptional and post-translational levels. These regulatory mechanisms also include epigenetic and microenvironmental signals. Several transcription factors and signaling pathways involved in the regulation of MITF expression and/or activity such as the Wnt/β-catenin pathway are broadly utilized by various types of tumors, whereas others, e.g., BRAFV600E/ERK1/2 are more specific for melanoma. Furthermore, the MITF activity can be affected by the availability of transcriptional co-partners that are often redirected by MITF from their own canonical signaling pathways. In this review, we discuss the complexity of a multilevel regulation of MITF expression and activity that underlies distinct context-related phenotypes of melanoma and might explain diverse responses of melanoma patients to currently used therapeutics.

Acid Ceramidase in Melanoma

“…This difference in subcellular localization might be related to recent work pointing to the existence of intriguing structural and functional links between AC and transcription factors that are important in melanocyte biology. These include the histone methyltransferase SETDB1 (SET domain bifurcated 1), which has been shown to accelerate melanoma onset (50) and was found to directly interact with AC (51), and MITF (microphthalmia-associated transcription factor), a master regulator of melanocyte terminal differentiation and pigmentation (52), which also plays a role in melanoma cell proliferation and survival (52,53) and was recently shown to up-regulate AC expression (54). Additional studies are needed to address the possibility that nuclear AC contributes to the regulation of gene expression in normal melanocytes.…”

miR-579-3p controls melanoma progression and resistance to target therapy

“…In this regard, a possible role could be played by the microphthalmia-associated transcription factor (MITF), a known master regulator of melanocyte development (45). MITF's role in the establishment of resistance to targeted therapies in melanoma is The model of miR-579-3p expression during melanoma progression and in the establishment of resistance to target therapies.…”

Genetics and epigenetics of melanoma

“…Reasons behind the phenotypic plasticity are largely unknown, although involvement of the melanosomal, lineage-specific transcription factor, MITF, have been suggested (31). In the present model, a low expression of the melanotic lineage-related transcription factor MITF was associated with invasive and stem cell markers and ZEB2 whereas a high MITF expression was associated with differentiation markers, high proliferative capacity and a high ZEB1 expression (32).…”