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RETRACTED ARTICLE: Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer

Cancer Gene Therapy volume 29, pages 543–557 (2022)Cite this article

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This article was retracted on 21 September 2023

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Abstract

Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis.

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Fig. 1: The correlation between KDM1B and clinical features of PC patients.
Fig. 2: Abnormal expression of KDM1B regulates proliferation and survival of prostate cancer cells.
Fig. 3: KDM1B suppressing inhibits AGR2 transcription in vitro and vivo.
Fig. 4: KDM1B promotes androgen-dependent AGR2 expression through recruitment of AR to the AGR2 gene promoter.
Fig. 5: Enzalutamide-resistant VCaP cells show relatively low levels of miR-215 and high levels of KDM1B.
Fig. 6: KDM1B inhibitor enhances enzalutamide-resistant VCaP cells response to enzalutamide in vitro and in vivo.

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Data generated for the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank professor Mixson James (University of Maryland School of Medicine, USA) to give us a language editing and members of Cui and He laboratories for discussion and comments on the paper.

Funding

Support by the National Natural Science Foundation of China (No. 81370804), the Guangdong Provincial Science and Technology Plan Project (No. 2017B030314108), and the High-level Hospital Construction Project of Guangdong Provincial People’s Hospital (KJ012021011) is gratefully acknowledged.

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Author notes

  1. These authors contributed equally: Donge Tang, Jiaxi He, Yong Dai

Authors and Affiliations

  1. Research Center of Medical Sciences, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Donge Tang & Songhui Xu

  2. Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People’s Hospital, Shenzhen, Guangdong, China

    Donge Tang & Yong Dai

  3. Department of Pathology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Jiaxi He, Qixin Leng & Songhui Xu

  4. Department of Biochemistry, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Xinyan Geng

  5. Department of Anesthesiology and Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA

    Haowu Jiang

  6. Department of Internal Medicine, Yale University, New Haven, CT, USA

    Rui Sun

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Contributions

S.H.X. and D.E.T. conceived and designed the experiments, S.H.X. analyzed the data and prepared the paper; D.E.T., Y.D., J.X.H., and X.Y.G. performed the experiments; H.W.J. and R.S. provided the statistical support; D.E.T. and Y.D. collected the sample tissues; Q.X.L. analyzed the IHC data. All authors read and approved the final paper.

Corresponding author

Correspondence to Songhui Xu.

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Ethics approval and consent to participate. For the use of these clinical materials for research purposes, prior patient consent and approval from the medical ethics committee of Shenzhen People’s Hospital. Animal studies were approved by the Animal Care and Use Committee of the College of Jinan University.

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Tang, D., He, J., Dai, Y. et al. RETRACTED ARTICLE: Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer. Cancer Gene Ther 29, 543–557 (2022). https://doi.org/10.1038/s41417-021-00332-6

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