Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions

Author:

Xu Wen12,Liu Li3,Cui Zhongqi4,Li Mingyang5,Ni Jinliang12,Huang Nan4,Zhang Yue4,Luo Jie4,Sun Limei4,Sun Fenyong627

Affiliation:

1. Shanghai Clinical College, Anhui Medical University , Shanghai , 200072 , China

2. The Fifth School of Clinical Medicine, Anhui Medical University , Hefei , 230032, Anhui , China

3. Department of Clinical Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University , Shanghai , 200127 , China

4. Department of Clinical Laboratory, Shanghai Tenth People’s Hospital of Tongji University , 200072 , Shanghai , China

5. School of Life Sciences, Jiangsu University , Zhenjiang , Jiangsu, 212013 , China

6. Shanghai Clinical College, Anhui Medical University , No. 301, Yanchang Middle Road, Jingan District , Shanghai , 200072 , China

7. Department of Clinical Laboratory, Shanghai Tenth People’s Hospital of Tongji University , No. 301, Yanchang Middle Road, Jingan District, 200072 , Shanghai , China

Abstract

Abstract Patients with castration-resistant prostate cancer (CRPC) often develop drug resistance after treatment with enzalutamide. The goal of our study was to identify the key genes related to enzalutamide resistance in CRPC and to provide new gene targets for future research on improving the efficacy of enzalutamide. Differential expression genes (DEGs) associated with enzalutamide were obtained from the GSE151083 and GSE150807 datasets. We used R software, the DAVID database, protein–protein interaction networks, the Cytoscape program, and Gene Set Cancer Analysis for data analysis. The effect of RAD51 knockdown on prostate cancer (PCa) cell lines was demonstrated using Cell Counting Kit-8, clone formation, and transwell migration experiments. Six hub genes with prognostic values were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which were significantly associated with immune cell infiltration in PCa. High RAD51, BLM, EXO1, and RFC2 expression was associated with androgen receptor signaling pathway activation. Except for APOE, high expression of hub genes showed a significant negative correlation with the IC50 of Navitoclax and NPK76-II-72-1. RAD51 knockdown inhibited the proliferation and migration of PC3 and DU145 cell lines and promoted apoptosis. Additionally, 22Rv1 cell proliferation was more significantly inhibited with RAD51 knockdown than without RAD51 knockdown under enzalutamide treatment. Overall, six key genes associated with enzalutamide resistance were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which are potential therapeutic targets for enzalutamide-resistant PCa in the future.

Publisher

Walter de Gruyter GmbH

Subject

General Medicine

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