BET Inhibition Might Be Active Against Renal Cell Carcinoma
Study findings suggest that BET inhibitors might be a promising avenue of drug-development against RCC.
Targeting bromodomain-4 protein (BRD4) expression with the BET inhibitor JQ1 reduces tumor cell proliferation and induces apoptosis in renal cell carcinoma (RCC), according to preclinical cell-line and xenograft experiments reported in Cellular Physiology and Biochemistry.
“Our research reveals that BRD4 probably plays a critical role in RCC progression, and is a new promising target for pharmacological treatment directed against this intractable disease,” reported corresponding study coauthor Fuqing Zeng, MD, of the department of urology at the Huazhong University of Science and Technology in China, and coauthors.
The molecular mechanisms underlying RCC drug resistance are poorly understood and there is a pressing need for development of new therapeutic targets and drugs.
BRD4 is a “highly-conserved and well-known” epigenome reader, believed to play a role in mitotic transcription regulation, the authors noted. In previous research, BRD4 expression was tied progression in non-RCC cancer types, such as glioblastoma.
The study team evaluated the possible roles of BRD4 expression and inhibition in RCC. In cell-line and xenograft studies, the team measured RCC BRD4 expression using qualitative real-time polymerase chain reaction (qRT-PCR) and western blot protein analysis. They also assessed BRD4 inhibition with the BET inhibitor JQ1.
“Inhibition of BRD4 suppressed RCC cell proliferation, induced cell apoptosis in vitro and repressed tumor growth in vivo,” they reported.
BRD4 inhibition with JQ1 decreased B cell lymphoma 2 gene (BCL2) and C-MYC expression, upregulated BCL2-associated X protein (BAX), and cleaved caspase3 expression, according to the study authors. That suggested that BRD4's role in RCC tumor biology involves BCL2 and C-MYC expression and “activating a group of apoptosis-associated protein kinases,” consistent with previous research.
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Drugs that target BET proteins are in clinical development, the authors noted. The study findings suggest that BET inhibitors might be a promising avenue of drug-development against RCC.
- Wu X, Liu D, Gao X, et al. Inhibition of BRD4 suppresses cell proliferation and induces apoptosis in renal cell carcinoma. Cell Physiol Biochem. 2017;41:1947-56. doi: 10.1159/000472407