High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma

Abstract

Cutaneous melanoma is an aggressive tumor that accounts for most skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes such as MITF that specify melanocyte identity, a phenomenon known in melanoma biology as lineage dependency. MITF overexpression is occasionally explained by gene amplification, but here we show that super-enhancers are also important determinants of MITF overexpression in some melanoma cell lines and tumors. Although compounds that directly inhibit MITF are unavailable, a covalent CDK7 inhibitor, THZ1, has recently been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We also show that melanoma cells are highly sensitive to CDK7 inhibition both in vitro and in vivo and that THZ1 can dismantle the super-enhancer apparatus at MITF and SOX10 in some cell lines, thereby extinguishing their intracellular levels. 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. Keywords: ChIP-seq; chromatin immunoprecipitation sequencing; CTD; carboxy-terminal domain; GI50; GSEA; gene set enrichment analysis; MITF-hi; high MITF expression level; MITF-lo; low MITF expression level; Pol IIpolymerase II; super-enhancer; Serserine; siRNA; small interfering RNA