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

Xiangpeng Dai1, Zhiwei Wang2,3, Wenyi Wei1

  • 1a Department of Pathology , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.

Cell Cycle (Georgetown, Tex.)
|November 8, 2017
PubMed

Insights

Prostate cancer cells with SPOP mutations accumulate BRD4, resisting BET inhibitors. Restoring SPOP function could improve cancer treatment strategies targeting BET proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Bromodomain and extra-terminal (BET) proteins are key drivers in various cancers, making them promising therapeutic targets.
  • Aberrant overexpression of BET proteins is common in human cancers, but the underlying mechanisms remain largely unclear.
  • Prostate cancer presents a significant unmet need for targeted therapies.

Purpose of the Study:

  • To investigate the role of SPOP (speckle-typePOZ protein) mutations in the context of BET protein overexpression in prostate cancer.
  • To elucidate the molecular mechanisms by which SPOP regulates BET protein stability.
  • To explore the therapeutic implications of SPOP mutations for BET inhibitor efficacy.

Main Methods:

  • Utilized prostate cancer cell lines with wild-type and mutant SPOP.
  • Investigated the interaction between SPOP mutants and BRD4 (a key BET protein).
  • Assessed the impact of SPOP status on BRD4 protein degradation and accumulation.
  • Evaluated the sensitivity of prostate cancer cells with SPOP mutations to BET inhibitors.

Main Results:

  • Prostate cancer-derived SPOP mutants exhibit impaired interaction with BRD4.
  • SPOP mutations prevent the degradation of BRD4, leading to its accumulation in cancer cells.
  • Cells harboring SPOP mutations demonstrate increased resistance to BET inhibitors.
  • SPOP functions as a tumor suppressor by negatively regulating BET protein stability.

Conclusions:

  • SPOP mutations contribute to BET protein overexpression and confer resistance to BET inhibitors in prostate cancer.
  • SPOP acts as a negative regulator of BET protein stability, highlighting its tumor suppressor role.
  • Targeting SPOP mutations may offer a novel therapeutic strategy, potentially in combination with BET inhibitors, for treating specific prostate cancer patient populations.
Keywords:
BETCell proliferationResistanceSPOPUbiquitin

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