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

https://doi.org/10.1016/j.jid.2017.09.056Get rights and content
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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.

Abbreviations

ChIP-seq
chromatin immunoprecipitation sequencing
CTD
carboxy-terminal domain
GI50
concentration at which half maximal inhibition of cell proliferation is achieved
GSEA
gene set enrichment analysis
MITF-hi
high MITF expression level
MITF-lo
low MITF expression level
Pol II
polymerase II
SE
super-enhancer
Ser
serine
siRNA
small interfering RNA

Cited by (0)

10

These authors contributed equally to this work as co-first authors.

11

These authors contributed equally to this work as co-senior authors.