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Targeted inhibition of the CREB1-CtIP axis enhances the efficacy of abiraterone combined with radiotherapy in prostate cancer
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  • Published: 30 March 2026

Targeted inhibition of the CREB1-CtIP axis enhances the efficacy of abiraterone combined with radiotherapy in prostate cancer

  • Xu Han  ORCID: orcid.org/0009-0008-4048-31621 na1,
  • Liang Song1 na1,
  • Yuankang Feng1,2 na1,
  • Zihao Wang1,
  • Lina Wang3,
  • Ruoyang Liu1,
  • Yu Liu1,
  • Ningyang Li1,
  • Saiyu Ma4,
  • Fubo Lu1,
  • Jinjian Yang  ORCID: orcid.org/0000-0003-4416-814X1,
  • Zhenlin Huang1 &
  • …
  • Zhankui Jia  ORCID: orcid.org/0000-0001-9545-61631 

Cell Death & Disease , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Prostate cancer

Abstract

In the treatment of locally advanced prostate cancer (PCa), abiraterone acetate (AA) serves both as a commonly used therapeutic agent and a radiosensitizer when combined with radiation therapy (RT). However, this combination therapy is not effective for all patients, and prolonged treatment may lead to decreased therapeutic sensitivity. Our study found that the combination of abiraterone (Abi, the active component of abiraterone acetate in vivo) and RT increases the expression of CtBP-interacting protein (CtIP) in prostate cancer cells, and elevated CtIP levels in PCa are associated with poor prognosis. CtIP has been demonstrated to be a key protein in the homologous recombination repair (HR) pathway of DNA damage repair (DDR). Furthermore, we observed that both Abi and RT enhance the transcriptional activity of CREB1 via phosphorylation, thereby modulating CtIP expression. Additionally, during the transition from normal prostate cells to prostate cancer cells, DNA demethylases (TETs) reduce DNA methylation levels in the promoter region of CtIP, facilitating the binding of CREB1 to the CtIP promoter. Finally, our in vitro and in vivo experiments indicate that the CREB1 phosphorylation inhibitor 666-15 significantly enhances the therapeutic efficacy of Abi-RT combination therapy. In summary, our study reveals that inhibition of the CREB1-CtIP axis effectively improves the therapeutic outcomes of Abi-RT combination therapy, which may offer a novel clinical strategy for the treatment of prostate cancer.

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Data availability

The raw data generated in this study are available upon request from the corresponding author.

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Acknowledgements

The authors thank public data of TCGA, JASPAR, WikiPathways, Enrichr, Human TFDB, GEPIA, UCSC and Cistromedb. We thank Dr. Wan (wanxbo@zzu.edu.cn) from The First Affiliated Hospital of Zhengzhou University for gifting the plasmids and Hela cell.

Funding

This work was supported by National Natural Science Foundation of China (grant number: 882172564, 82303032, 82573338), Henan Science and Technology Research Program (grant number: 2018020142) and the Key Laboratory of Urinary Tumors, Henan Provincial Health Commission, Zhengzhou, Henan, China.

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  1. These authors contributed equally: Xu Han, Liang Song, Yuankang Feng.

Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Xu Han, Liang Song, Yuankang Feng, Zihao Wang, Ruoyang Liu, Yu Liu, Ningyang Li, Fubo Lu, Jinjian Yang, Zhenlin Huang & Zhankui Jia

  2. Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China

    Yuankang Feng

  3. Department of General Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China

    Lina Wang

  4. Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China

    Saiyu Ma

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Contributions

XH and ZLH conceived and designed the study. XH, LS, and YKF performed experiments and drafted the manuscript. XH, ZHW, YL, and FBL performed experiments and analyzed the data. LS, LNW, and YL performed the statistical analysis. RYL, NYL, and SYM provided technical and methodological support. JJY supervised the study. ZKJ and ZLH reviewed and revised the manuscript. All authors read and approved the final version.

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Correspondence to Jinjian Yang, Zhenlin Huang or Zhankui Jia.

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Approval was obtained for all animal studies under the guidelines of the First Affiliated Hospital of Zhengzhou University. All clinical study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University and written informed consent was obtained from all subjects. Ethics approval number: 2024-KY-1207-001.

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Han, X., Song, L., Feng, Y. et al. Targeted inhibition of the CREB1-CtIP axis enhances the efficacy of abiraterone combined with radiotherapy in prostate cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08633-0

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  • Received: 14 July 2025

  • Revised: 23 February 2026

  • Accepted: 10 March 2026

  • Published: 30 March 2026

  • DOI: https://doi.org/10.1038/s41419-026-08633-0

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