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Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis

Oncogene volume 36, pages 6213–6224 (2017)Cite this article

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Abstract

Current therapeutic regimens for prostate cancer focus on targeting androgen receptor (AR) signaling. However, the AR is a key factor in luminal epithelium differentiation and was shown to have a role as a tumor suppressor. Thus, its inhibition may activate oncogenic pathways that contribute to metastatic castration-resistant prostate cancer (CRPC). Herein, we report a novel tumor promoter, ZBTB46, which is negatively regulated by AR signaling via microRNA (miR)-1-mediated downregulation. ZBTB46 is associated with malignant prostate cancer and is essential for metastasis. Its overexpression can overcome the antitumor effects of miR-1 and promote androgen-independent proliferation. We demonstrated that ZBTB46 can transcriptionally regulate SNAI1, a key epithelial-to-mesenchymal transition (EMT) driver, which could contribute to induction of the EMT after androgen-deprivation therapy and metastasis. Our findings are supportive of the model that disruption of AR’s function may predispose prostate cancer to progress to metastatic CRPC.

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Acknowledgements

This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan (MOST104-2314-B-038-045-MY3) to YNL, (MOST105-2320-B-038-044) to WYC, (MOST104-2320-B-038-055-MY3) to YCT, by the National Health Research Institutes of Taiwan (NHRI-EX106-10308BC) to YNL, by Taipei Medical University (TMU104-AE1-B22) to WYC, and by the Health and Welfare Surcharge of Tobacco Products (MOHW106-TDU-B-212-144001) to YNL.

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Author notes

  1. W-Y Chen and Y-C Tsai: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    W-Y Chen & C-L Chen

  2. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    W-Y Chen

  3. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Y-C Tsai, M K Siu & Y-N Liu

  4. Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    M K Siu

  5. Institute of Information System and Applications, National Tsing Hua University, Hsinchu, Taiwan

    H-L Yeh

  6. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    C-L Chen

  7. Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

    C-L Chen

  8. Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    J J Yin

  9. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    J Huang

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Correspondence to J Huang or Y-N Liu.

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Chen, WY., Tsai, YC., Siu, M. et al. Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis. Oncogene 36, 6213–6224 (2017). https://doi.org/10.1038/onc.2017.226

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