期刊
CANCER LETTERS
卷 440, 期 -, 页码 35-46出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.10.004
关键词
Androgen deprivation therapy (ADT); Neuroendocrine prostate cancer (NEPC); ZBTB46; SPDEF; PTGS1
类别
资金
- Ministry of Science and Technology of Taiwan [MOST105-2628-B-038-006-MY3, MOST107-2628-B-038-001, MOST107-2320-B-038-058]
- Taipei Medical University-Wan Fang Hospital [107TMU-WFH-03]
- National Health Research Institute of Taiwan [NHRI-EX107-10702BI]
- TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program by the Ministry of Education (MOE) in Taiwan
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 incompletely 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 associated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coactivator 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.
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