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

Oncogene volume 41, pages 3251–3262 (2022)Cite this article

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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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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clinicians. 2018;68:394–424.

    Google Scholar 

  2. Holmes L Jr., Chan W, Jiang Z, Du XL. Effectiveness of androgen deprivation therapy in prolonging survival of older men treated for locoregional prostate cancer. Prostate Cancer Prostatic Dis. 2007;10:388–95.

    Article  CAS  PubMed  Google Scholar 

  3. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009;6:76–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl J Med. 2011;364:1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.

    Article  CAS  PubMed  Google Scholar 

  7. Cai L, Tsai YH, Wang P, Wang J, Li D, Fan H, et al. ZFX mediates non-canonical oncogenic functions of the androgen receptor splice variant 7 in castrate-resistant prostate cancer. Mol Cell. 2018;72:341–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4:365–80.

    PubMed  PubMed Central  Google Scholar 

  9. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45.

    Article  CAS  PubMed  Google Scholar 

  10. Huang Y, Jiang X, Liang X, Jiang G. Molecular and cellular mechanisms of castration resistant prostate cancer. Oncol Lett. 2018;15:6063–76.

  11. Zhang J, Kuang Y, Wang Y, Xu Q, Ren Q. Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-kappaB pathway. Apoptosis. 2017;22:877–84.

    Article  CAS  PubMed  Google Scholar 

  12. Alajati A, D’Ambrosio M, Troiani M, Mosole S, Pellegrini L, Chen J, et al. CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo. J Clin Investig. 2020;130:2435–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Siva AC, Wild MA, Kirkland RE, Nolan MJ, Lin B, Maruyama T, et al. Targeting CUB domain-containing protein 1 with a monoclonal antibody inhibits metastasis in a prostate cancer model. Cancer Res. 2008;68:3759–66.

    Article  CAS  PubMed  Google Scholar 

  14. Ikeda J, Oda T, Inoue M, Uekita T, Sakai R, Okumura M, et al. Expression of CUB domain containing protein (CDCP1) is correlated with prognosis and survival of patients with adenocarcinoma of lung. Cancer Sci. 2009;100:429–33.

    Article  CAS  PubMed  Google Scholar 

  15. Scherl-Mostageer M, Sommergruber W, Abseher R, Hauptmann R, Ambros P, Schweifer N. Identification of a novel gene, CDCP1, overexpressed in human colorectal cancer. Oncogene. 2001;20:4402–8.

    Article  CAS  PubMed  Google Scholar 

  16. Kryza T, Khan T, Puttick S, Li C, Sokolowski KA, Tse BW, et al. Effective targeting of intact and proteolysed CDCP1 for imaging and treatment of pancreatic ductal adenocarcinoma. Theranostics. 2020;10:4116–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wright HJ, Arulmoli J, Motazedi M, Nelson LJ, Heinemann FS, Flanagan LA, et al. CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer. Oncogene. 2016;35:4762–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Awakura Y, Nakamura E, Takahashi T, Kotani H, Mikami Y, Kadowaki T, et al. Microarray-based identification of CUB-domain containing protein 1 as a potential prognostic marker in conventional renal cell carcinoma. J Cancer Res Clin Oncol. 2008;134:1363–9.

    Article  CAS  PubMed  Google Scholar 

  19. Cao M, Gao J, Zhou H, Huang J, You A, Guo Z, et al. HIF-2alpha regulates CDCP1 to promote PKCdelta-mediated migration in hepatocellular carcinoma. Tumour Biol. 2016;37:1651–62.

    Article  CAS  PubMed  Google Scholar 

  20. Gioia R, Leroy C, Drullion C, Lagarde V, Etienne G, Dulucq S, et al. Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. Blood. 2011;118:2211–21.

    Article  CAS  PubMed  Google Scholar 

  21. Heitmann JS, Hagelstein I, Hinterleitner C, Roerden M, Jung G, Salih HR, et al. Identification of CD318 (CDCP1) as novel prognostic marker in AML. Ann Hematol. 2020;99:477–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Uekita T, Sakai R. Roles of CUB domain-containing protein 1 signaling in cancer invasion and metastasis. Cancer Sci. 2011;102:1943–8.

    Article  CAS  PubMed  Google Scholar 

  23. Liu H, Ong SE, Badu-Nkansah K, Schindler J, White FM, Hynes RO. CUB-domain-containing protein 1 (CDCP1) activates Src to promote melanoma metastasis. Proc Natl Acad Sci USA. 2011;108:1379–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Casar B, Rimann I, Kato H, Shattil SJ, Quigley JP, Deryugina EI. In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated beta1 integrin and induction of FAK/PI3K/Akt motility signaling. Oncogene. 2014;33:255–68.

    Article  CAS  PubMed  Google Scholar 

  25. Razorenova OV, Finger EC, Colavitti R, Chernikova SB, Boiko AD, Chan CKF, et al. VHLloss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration. Proc Natl Acad Sci. 2011;108:1931–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Leroy C, Shen Q, Strande V, Meyer R, McLaughlin ME, Lezan E, et al. CUB-domain-containing protein 1 overexpression in solid cancers promotes cancer cell growth by activating Src family kinases. Oncogene. 2015;34:5593–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He Y, Wortmann A, Burke LJ, Reid JC, Adams MN, Abdul-Jabbar I, et al. Proteolysis-induced N-terminal ectodomain shedding of the integral membrane glycoprotein CUB domain-containing protein 1 (CDCP1) is accompanied by tyrosine phosphorylation of its C-terminal domain and recruitment of Src and PKCdelta. J Biol Chem. 2010;285:26162–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Khan T, Kryza T, Lyons NJ, He Y, Hooper JD. The CDCP1 signaling hub: a target for cancer detection and therapeutic intervention. Cancer Res. 2021;81:2259–69.

    Article  CAS  PubMed  Google Scholar 

  29. Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513:124–8.

    Article  CAS  PubMed  Google Scholar 

  30. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    Article  CAS  PubMed  Google Scholar 

  31. Donati B, Lorenzini E, Ciarrocchi A. BRD4 and Cancer: going beyond transcriptional regulation. Mol Cancer. 2018;17:164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Iyer NG, Ozdag H, Caldas C. p300/CBP and cancer. Oncogene. 2004;23:4225–31.

    Article  CAS  PubMed  Google Scholar 

  33. Welti J, Sharp A, Brooks N, Yuan W, McNair C, Chand SN, et al. Targeting the p300/CBP axis in lethal prostate cancer. Cancer Disco. 2021;11:1118–37.

    Article  CAS  Google Scholar 

  34. Ren C, Zhang G, Han F, Fu S, Cao Y, Zhang F, et al. Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth. Proc Natl Acad Sci USA. 2018;115:7949–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Spriano F, Gaudio E, Cascione L, Tarantelli C, Melle F, Motta G, et al. Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734. Blood Adv. 2020;4:4124–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shorstova T, Foulkes WD, Witcher M. Achieving clinical success with BET inhibitors as anti-cancer agents. Br J Cancer. 2021;124:1478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zaware N, Zhou MM. Bromodomain biology and drug discovery. Nat Struct Mol Biol. 2019;26:870–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jin L, Garcia J, Chan E, de la Cruz C, Segal E, Merchant M, et al. Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer. Cancer Res. 2017;77:5564–75.

    Article  CAS  PubMed  Google Scholar 

  40. Yang C, Li S, Wang M, Chang AK, Liu Y, Zhao F, et al. PTEN suppresses the oncogenic function of AIB1 through decreasing its protein stability via mechanism involving Fbw7 alpha. Mol Cancer. 2013;12:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gusenbauer S, Vlaicu P, Ullrich A. HGF induces novel EGFR functions involved in resistance formation to tyrosine kinase inhibitors. Oncogene. 2013;32:3846–56.

    Article  CAS  PubMed  Google Scholar 

  42. Wu D, Yan Y, Wei T, Ye Z, Xiao Y, Pan Y, et al. An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors. Cell Rep. 2021;34:108744.

    Article  CAS  PubMed  Google Scholar 

  43. Zucconi BE, Makofske JL, Meyers DJ, Hwang Y, Wu M, Kuroda MI, et al. Combination targeting of the bromodomain and acetyltransferase active site of p300/CBP. Biochemistry. 2019;58:2133–43.

    Article  CAS  PubMed  Google Scholar 

  44. Devaiah BN, Mu J, Akman B, Uppal S, Weissman JD, Cheng D, et al. MYC protein stability is negatively regulated by BRD4. Proc Natl Acad Sci USA. 2020;117:13457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Garcia-Carpizo V, Ruiz-Llorente S, Sarmentero J, González-Corpas A, Barrero MJ. CREBBP/EP300 bromodomain inhibition affects the proliferation of AR-positive breast cancer cell lines. Mol Cancer Res. 2019;17:720–30.

    Article  CAS  PubMed  Google Scholar 

  46. Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, Crouthame MC, et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013;4:2419–29.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hay DA, Fedorov O, Martin S, Singleton DC, Tallant C, Wells C, et al. Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains. J Am Chem Soc. 2014;136:9308–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hammitzsch A, Tallant C, Fedorov O, O’Mahony A, Brennan PE, Hay DA, et al. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci USA. 2015;112:10768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32:5501–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations

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

    Donglei Ji, Guanglei Shang, Enwei Wei, Yanjie Jia, Qiang Zhang & Lei Zeng

  2. International Center of Future Science, Jilin University, Changchun, 130012, China

    Donglei Ji, Guanglei Shang, Enwei Wei & Lei Zeng

  3. State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, Jilin, 130012, China

    Chunyu Wang

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Contributions

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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