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Abstract
While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression.
The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.
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1 University of Rochester, George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, Biology and The Wilmot Cancer Institute, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174)
2 University of Rochester, George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, Biology and The Wilmot Cancer Institute, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174); The 4th Affiliated Hospital of Harbin Medical University, Department of Urology, Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268)
3 Shanxi Province People’s Hospital, Department of Urology, Xi’an, China (GRID:grid.16416.34)
4 The 4th Affiliated Hospital of Harbin Medical University, Department of Urology, Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268)
5 Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China (GRID:grid.265021.2) (ISNI:0000 0000 9792 1228)
6 Indiana University, Department of Pathology & Laboratory Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
7 The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776)
8 Jiangmen Maternity and Child Health Care Hospital, Jiangmen, China (GRID:grid.240145.6)
9 University of Rochester, George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, Biology and The Wilmot Cancer Institute, Rochester, USA (GRID:grid.16416.34) (ISNI:0000 0004 1936 9174); China Medical University and Hospital, Sex Hormone Research Center, Taichung, Taiwan (GRID:grid.411508.9) (ISNI:0000 0004 0572 9415)