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Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer

Donglei Ji1,2, Guanglei Shang1,2, Enwei Wei1,2

  • 1Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, Jilin, 130021, China.

Oncogene
|May 5, 2022
PubMed

Insights

Transcription cofactors BRD4 and CBP/p300 drive prostate cancer progression by increasing CUB domain-containing protein 1 (CDCP1) expression. Dual inhibition of BRD4 and CBP/p300 offers a promising therapeutic strategy for castrate-resistant prostate cancer (CRPC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • CUB domain-containing protein 1 (CDCP1) is a transmembrane protein implicated in tumor metastasis.
  • CDCP1 is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC), but the underlying mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving CDCP1 overexpression in CRPC.
  • To investigate the role of transcription cofactors BRD4 and CBP/p300 in CDCP1 regulation.
  • To evaluate the therapeutic potential of targeting BRD4 and CBP/p300 in CRPC.

Main Methods:

  • Analysis of CDCP1 expression in CRPC.
  • Investigating the correlation between BRD4, CBP/p300 expression, and CDCP1 gene amplification.
  • CRISPR-based knockdown and pharmacological inhibition of BRD4 and CBP/p300.
  • Biochemical and structural analyses of dual-inhibitor NEO2734.
  • Assessment of downstream signaling pathways (PI3K/AKT, SRC/MAPK) and CRPC cell proliferation/metastasis.

Main Results:

  • BRD4 and CBP/p300 co-regulate CDCP1 transcription in CRPC.
  • Increased BRD4 and CBP/p300 expression correlates with CDCP1 gene amplification.
  • Dual inhibition of BRD4 and CBP/p300 significantly down-regulates CDCP1 and its downstream pathways compared to single inhibition.
  • NEO2734, a dual inhibitor, demonstrates superior efficacy in suppressing CDCP1 expression and CRPC progression.

Conclusions:

  • BRD4 and CBP/p300 are key regulators of CDCP1 in CRPC tumorigenesis.
  • Targeting CDCP1 via dual inhibition of BRD4 and CBP/p300 presents a synergistic therapeutic strategy for CRPC.
  • This approach holds promise for developing novel treatments for advanced prostate cancer.

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