SPOP-mediated degradation of BRD4 dictates cellular sensitivity to BET inhibitors.

Bromodomain and extra-terminal (BET) proteins are frequently overexpressed in various human cancers, therefore have been clinically pursed as attractive therapeutic anti-cancer targets. However, relatively little is known about the mechanism(s) underlying aberrant BET overexpression in human cancers. Recently, we reported that prostate cancer-derived SPOP mutants fail to interact with and promote BRD4 degradation, leading to accumulation of BRD4 in prostate cancer cells. As a result, prostate cancer cells harboring SPOP mutations are more resistant to BET inhibitors. Therefore, our results help to elucidate the tumor suppressor role of SPOP in the prostate cancer setting by negatively controlling BET proteins stability. More importantly, our results also provide a molecular basis for using combination with BET inhibitors and other inhibitors to treat prostate cancer patients with SPOP mutations.