Human MITF blocking peptide

Acidosis of the tumor microenvironment is a characteristic of solid tumors such as malignant melanoma. Main causes of the extracellular acidification are metabolic alterations in cancer cells. While numerous studies showed that acidosis promotes tumor invasiveness, metastasis, and neoangiogenesis resulting in malignant progression, contrary data reported that acidosis induces cell apoptosis, inhibits cell proliferation, and mediates cell autophagy. Here, we show that low pH (pH 6.7) induces senescent/quiescent phenotype in melanoma cells after long-time treatment defined by induction of SA-beta-galactosidase, upregulation of p21, G(1)/G(0) cell cycle arrest, and reduction of proliferation. Moreover, we revealed that extracellular acidosis triggers the inhibition of eIF2 alpha and subsequently the activation of ATF4 expression, a key component of the integrated stress response (ISR), indicating an acid-mediated translation reprogramming. Interestingly, we also demonstrated that acidosis represses microphthalmia-associated transcription factor (MITF) and activates the expression of the receptor tyrosine kinase AXL. This MITFlow/AXL(high) phenotype is correlated with drug resistance and therapeutic outcome in melanoma. Our results suggest that acidosis is an important microenvironmental factor triggering phenotypic plasticity and promoting tumor progression.

Melanoma, a melanocyte-origin neoplasm, is a highly metastatic and treatment-resistance cancer. While it is well established that notch signaling activation promotes melanoma progression, little is known about the reciprocal interactions between Notch signaling and melanoma-specific pathways. Here we reveal a negative regulatory loop between Notch signaling and microphthalmia-associated transcription factor (MITF), the central regulator of melanoma progression and the driver of melanoma plasticity. We further demonstrate that Notch signaling activation, in addition to the known competition-based repression mechanism of MITF transcriptional activity, inhibits the transcription of MITF, leading to a decrease in MITF expression. We also found that MITF binds to the promoter of the gene encoding the master regulator of Notch signaling, recombination signal binding protein J kappa (RBPJK), leading to its upregulation. Our findings suggest that, once activated, Notch signaling represses MITF signaling to maintain the melanoma invasiveness and metastatic phenotype.