High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma
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Author(s)
Eliades, Philip
Abraham, Brian J.
Ji, Zhenyu
Christensen, Camilla L.
Kwiatkowski, Nicholas
Kumar, Raj
Njauw, Ching Ni
Taylor, Michael
Miao, Benchun
Zhang, Tinghu
Date Issued
March 2018
Journal
Journal of Investigative Dermatology
Publisher
Elsevier BV
Citation
Eliades, Philip et al. “High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma.” Journal of Investigative Dermatology 138, 7 (July 2018): 1582–1590 © 2018 The Authors
Version
Author's final manuscript
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
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.JID.2017.09.056
