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  • br Denham JW Joseph D

    2022-05-19


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    Contents lists available at ScienceDirect
    Cancer Letters
    journal homepage: www.elsevier.com/locate/canlet
    Original Articles
    Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes T
    neuroendocrine differentiation of prostate cancer
    Wei-Yu Chena,b, Tao Zengc, Yu-Chng Wend,e, Hsiu-Lien Yehf, Kuo-Ching Jiangg, Wei-Hao Cheng, Qingfu Zhangh, Jiaoti Huangi, Yen-Nien Liug,j,∗ a Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
    b Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
    c Department of Urology, The People's Hospital of Jiangxi Province, Nanchang, China
    d Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
    e Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
    f Institute of Information System and Applications, National Tsing Hua University, Hsinchu, Taiwan
    g Graduate Institute of Molecular Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
    h Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China
    i Department of Pathology, Duke University Medical Center, Durham, NC, USA
    j TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
    Keywords:
    Androgen deprivation therapy (ADT)
    Neuroendocrine prostate cancer (NEPC)
    SPDEF
    Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains in-completely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. We demonstrated a molecular mechanism whereby ZBTB46 can be regulated by the androgen-responsive gene, SPDEF, and is as-sociated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coacti-vator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. Overexpression of ZBTB46 decreases the sensitivity of the combination of enzalutamide and a PTGS1 inhibitor; however, knockdown of ZBTB46 sensitizes the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 is inversely correlated with SPDEF and is increased in higher tumor grades and small-cell NE prostate cancer (SCNC) patients, which are positively associated with PTGS1. Our findings suggest that the induction of ZBTB46 results in increased PTGS1 expression, which is associated with NEPC progression and linked to the dysregulation of the AR-SPDEF pathway.