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

Abstract

CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC.

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Fig. 1: CDCP1 is highly expressed in AR negative prostate cancer cell lines.
Fig. 2: BRD4 and CBP/p300 co-regulate CDCP1 transcriptional activation.
Fig. 3: Dual-targeting BRD4 and CBP/p300 downregulate oncogenic signaling and cell viability in PCa.
Fig. 4: Structural insights into NEO2734 binding to BRD4-BD1 or CBP-BrD.
Fig. 5: NEO2734 leads to down-regulation of cell growth pathways in PCa.

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Acknowledgements

We thank the technical support of BL17U beamline at the Shanghai Synchrotron Radiation Light Source with X-ray data collection, Dr. Fangbin Han for providing SGC-CBP30 and I-BET762 compounds, Ying Zhao for providing LNCaP cells. We would like to acknowledge BGI Group for generating RNA-seq data. We thank Prof. Ming-Ming Zhou for discussion in this study and editing the manuscript.

Funding

This work was supported in part by the research fund from the First Hospital of Jilin University (Changchun, China), the Open Project of State Key Laboratory for Supramolecular Structure and Materials, JLU (SKLSSM201602), JLU Science and Technology Innovative Research Team (JLUSTIRT, 2017TD-25), International Center of Future Science, JLU, and National Natural Science Foundation of China (31770780; L.Z.).

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LZ conceived the project. DJ performed experiments. DJ and EW performed qRT-PCR experiments. DJ and GS collected and analyzed X-Ray data. DJ, YJ, QZ, and CW for expression and purification proteins. DJ and LZ wrote the manuscript with input from all co-authors.

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Correspondence to Lei Zeng.

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Ji, D., Shang, G., Wei, E. et al. Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer. Oncogene 41, 3251–3262 (2022). https://doi.org/10.1038/s41388-022-02327-5

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