Taken together, we provide evidence that p300/CBP inhibition suppressed the melanoma-driven transcription factor, MITF, and could be further exploited as a potential therapy for treating melanoma.
MITF is a lineage-specific master regulator of melanocytes and together with PGC-1alpha is a marker for melanoma subtypes with dependence for mitochondrial oxidative metabolism.
Furthermore, our results establish UVRAG as an important effector for melanocytes' response to α-MSH signaling as a direct target of MITF and reveal the molecular basis underlying the association between oncogenic BRAF and compromised UV protection in melanoma.
Our results show a dimension to MITF regulation in melanoma cells and point to CDK7 inhibition as a potential strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.
The microphthalmia-associated transcription factorMITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma.
A downregulation of the melanoma oncogene microphthalmia-associated transcription factor (Mitf) was observed, and most likely caused by the inhibition of Id2, a gene that regulated HLH transcription factors such as MITF and also reported to promote tumor cell migration and invasion.
If MITF is used alone in the nail bed, its weak sensitivity may result in a false-negative interpretation and may be wrongly reassuring in the evaluation of early melanomas.
These data show that a change in MITF transcriptional activity from repression to activation of S100A4 that results from a point mutation in MITF alters melanoma invasive ability.
Thus, different combinations of therapies should be effective in treating different phases of melanoma, such as the combination of targeted therapies with inhibitors of MITF expression during the initial treatment phase, but with inhibitors of WNT5A/AXL/NF-κB signaling during relapse.
Our findings present a new putative function for PHBs as regulators of LC3/ERK/MITF melanogenic signaling, and suggest that Mel9 and Mel41 may provide the basis for the development of new drugs candidates to treat melanoma and other types of cancers.
Expression of <i>MITF</i> partially correlated with that of its known target genes, while <i>SOX10</i> expression correlated best with <i>PAX3</i> and <i>ZEB2</i> Nevertheless, cells simultaneously expressing <i>MITF</i>-high and <i>MITF</i>-low signature genes were observed both by single-cell analyses and RNAscope.<b>Conclusions:</b> Single-cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity.
Together, our results demonstrate that AR can promote melanoma metastasis via altering the miRNA-539-3p/USP13/MITF/AXL signal and targeting this newly identified signal with AR degradation enhancer ASC-J9 may help us to better suppress the melanoma metastasis.
Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells.
Finally, CONPs obviously suppressed the growth of human melanoma in tumor-bearing nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice, accompanied with tumors structural necrosis and fibrosis remarkably and decreased expression of CD271, SOX10 and MITF.
These results demonstrate the potential role of NAT10 in melanogenesis and melanoma growth through the regulation of microphthalmia-associated transcription factor (MITF) expression and provide a promising strategy for the treatment of various skin diseases (melanoma) and pigmentation disorders (chloasma and freckles).
This is just one of the possible roles of SOX10, which contributes to melanomagenesis by regulating the SOX10-MITF pathway, but also to melanoma cell survival, proliferation and metastasis formation.
In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITFE318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma.
Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose phenotypes include depigmentation due to melanocyte loss, whereas amplification or specific mutation of MITF can be an oncogenic event that is seen in a subset of familial or sporadic melanomas.
Indeed, drug combinations targeting both mutant BRAF and MITF or one of its important targets Bcl-2 were effective in mutant BRAF melanoma but had no effect on acquired resistance.