Analysis of the Role of HDAC6 on MITF Pathway, in the Pathogenesis of Melanoma Open Access
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The histone deacetylase 6 (HDAC6), which belongs to class IIb family of HDACs is known to play a role in different cellular processes, involved in the pathogenesis of cancer and immune regulation. Recently, we found that treatment of cancer cells with HDAC6 inhibitors (HDAC6is) lead to an increase in acetylation of tubulin and decrease in the p-STAT3 –Y705 and PDL-1 expression, along with a decrease in tumor growth in melanoma-challenged mice models. On further investigations, we found that the treatment with HDAC6i Nexturastat A (Next A) leads to a significant decrease in pigmentation of the non-cancerous murine B16 melanocytes, along with a downregulation of the genes involved in the normal melanocytic development and pigmentation process. We were particularly interested in the Microphthalmia-Associated Transcription Factor (MITF), a melanocytic lineage-specific transcription factor, which also plays a critical role in malignant melanoma and leads to BRAF-inhibitor resistance. MITF, its target genes, as well as MITF protein expression were all decreased with KD of HDAC6 and on treatment with 5μM Next A, in the WM164 human melanoma cell lines, although there was no impact on the nuclear localization of MITF. Further, the molecular mechanisms by which HDAC6 regulates MITF, including interaction with other transcriptional factors such as STAT3, is being characterized. Thus, targeting HDAC6 with selective HDAC6 inhibitor will have a critical implication in the treatment of BRAF-resistant melanoma patients. Keywords: Melanoma, HDAC6, MITF.