Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 138, Issue 7, Pages 1582-1590Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2017.09.056
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Funding
- National Institutes of Health [K24-CA149202, P01-CA163222, T32-CA071345]
- Melanoma Research Alliance
- American Dermatological Association
- American Skin Association
- Hope Funds
- Hope Funds for Cancer Research Grillo-Marxuach Family Fellow
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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.
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