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


Eliades, Philip and Abraham, Brian J. and Ji, Zhenyu and Miller, David M. and Christensen, Camilla L. and Kwiatkowski, Nicholas and Kumar, Raj and Njauw, Ching Ni and Taylor, Michael and Miao, Benchun and Zhang, Tinghu and Wong, Kwok-Kin and Gray, Nathanael S. and Young, Richard A. and Tsao, Hensin


June 30, 2018


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. Eliades et al. (2018)


Eliades, Philip, Brian J. Abraham, Zhenyu Ji, David M. Miller, Camilla L. Christensen, Nicholas Kwiatkowski, Raj Kumar, et al. 2018. “High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma.” Journal of Investigative Dermatology 138 (7): 1582–90. https://doi.org/10.1016/j.jid.2017.09.056.