Objective: To explore the genetic changes in the progression of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) and the reason why these cancers resist existing therapies. Methods: We employed our CRPC cell line microarray and other CRPC or NEPC datasets to screen the target gene NEIL3. Lentiviral transfection and RNA interference were used to construct overexpression and knockdown cell lines. Cell and animal models of radiotherapy were established by using a medical electron linear accelerator. Flow cytometry was used to detect apoptosis or cell cycle progression. Western blot and qPCR were used to detect changes in the protein and RNA levels. Results: TCGA and clinical patient datasets indicated that NEIL3 was downregulated in CRPC and NEPC cell lines, and NEIL3 was correlated with a high Gleason score but a good prognosis. Further functional studies demonstrated that NEIL3 had no effect on the proliferation and migration of PCa cells. However, cell and animal radiotherapy models revealed that NEIL3 could facilitate the radiotherapy sensitivity of PCa cells, while loss of NEIL3 activated radiotherapy resistance. Mechanistically, we found that NEIL3 negatively regulated the expression of ATR, and higher NEIL3 expression repressed the ATR/CHK1 pathway, thus regulating the cell cycle. Conclusions: We demonstrated that NEIL3 may serve as a diagnostic or therapeutic target for therapy-resistant patients.

Qiong Wang;Zean Li;Jin Yang;Shirong Peng;Qianghua Zhou;Kai Yao;Wenli Cai;Zhongqiu Xie;Fujun Qin;Hui Li;Xu Chen;Kaiwen Li;Hai Huang

Department of Urology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China;Department of Pathology,School of Medicine,University of Virginia,Charlottesville,VA 22908,USA;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China;Department of Radiation Oncology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China;Department of Urology,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;Department of Radiology,Massachusetts General Hospital,Harvard Medical School,Boston,MA 02114,USA;Department of Urology,The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People's Hospital,Qingyuan 511518,China

癌症生物学与医学（英文版）

[1]Qiong Wang;Zean Li;Jin Yang;Shirong Peng;Qianghua Zhou;Kai Yao;Wenli Cai;Zhongqiu Xie;Fujun Qin;Hui Li;Xu Chen;Kaiwen Li;Hai Huang-.Loss of NEIL3 activates radiotherapy resistance in the progression of prostate cancer)[J].癌症生物学与医学（英文版）,2022(08):1193-1210

Lentiviral

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