Abstract
DUB3-mediated BRD4 stabilization overcomes SPOP-mediated degradation to confer BET inhibitor resistance.
Major finding: DUB3-mediated BRD4 stabilization overcomes SPOP-mediated degradation to confer BET inhibitor resistance.
Mechanism: The NCOR2–HDAC10 complex binds to and represses the DUB3 promoter, increasing BRD4 degradation.
Impact: Therapeutic targeting of DUB3 may sensitize SPOP-mutant prostate cancer to BET inhibitors.
BRD4 is an epigenetic reader protein in the BET family that has emerged as a therapeutic target in cancer. Prostate cancer–associated loss-of-function mutations in the E3 ubiquitin ligase SPOP impair ubiquitin-dependent proteasomal degradation of BRD4, thereby upregulating BRD4 levels and conferring resistance to BET inhibitors. It is not known whether a deubiquitinase could similarly stabilize BRD4. Jin and colleagues found that BRD4 is a substrate of the DUB3 deubiquitinase, showing that DUB3 interacted with BRD4 and specifically deubiquitinated and stabilized BRD4 in prostate cancer cells. Further, DUB3 activity suppressed SPOP-mediated BRD4 degradation. Expression of DUB3 was suppressed by binding of the NCOR2–HDAC10 complex to the DUB3 promoter. NCOR2 deletion occurs in a subset of patients with castration-resistant prostate cancer (CRPC), and immunohistochemistry of 53 prostate tumor samples revealed that NCOR2 expression was inversely associated with DUB3 and BRD4 levels. Moreover, in prostate cancer cells, depletion of NCOR2 increased expression of DUB3 and BRD4. CDK4/6-mediated phosphorylation of DUB3 is required for its catalytic activity, and accordingly CDK4/6 depletion or inhibition suppressed DUB3 activity, thereby accelerating BRD4 degradation and resulting in increased levels of BRD4. Consistent with these findings, DUB3 inhibition reduced BRD4 levels and sensitized prostate cancer cells to the BET inhibitor JQ1 both in vitro and in vivo in tumor xenografts, including in SPOP-mutant tumors. In addition to identifying DUB3 as a BRD4 deubiquitinase, these findings suggest the potential for therapeutic targeting of DUB3 to overcome BET inhibitor resistance, especially in SPOP-mutant prostate cancer.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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