DNA polymerase theta repression enhances the docetaxel responsiveness in metastatic castration-resistant prostate cancer

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Kuei, Chia-Hao^1,2  Lin, Hui-Yu^1,3  Lin, Min-Hsuan¹  Lee, Hsun-Hua^1,4,5,6,7  Lin, Che-Hsuan^8,9  Lee, Wei-Jiunn^10,11  Chen, Yen-Lin¹²  Lu, Long-Sheng¹³  Zheng, Jing-Quan^1,14  Hung, Ruei-Chen^1,8  Chiu, Hui-Wen^1,15  Chen, Kuan-Chou^1,10,16  Lin, Yuan-Feng^1,17 

[1] Taipei Med Univ, Coll Med, Grad Inst Clin Med, Taipei 11031, Taiwan

[2] Cardinal Tien Hosp, Dept Urol, Div Surg, New Taipei 23148, Taiwan

[3] Cardinal Tien Hosp, Dept Breast Surg & Gen Surg, Div Surg, New Taipei 23148, Taiwan

[4] Taipei Med Univ, Shuang Ho Hosp, Dept Neurol, New Taipei 23148, Taiwan

[5] Taipei Med Univ, Coll Med, Sch Med, Dept Neurol, New Taipei 23561, Taiwan

[6] Taipei Med Univ, Shuang Ho Hosp, Vertigo & Balance Impairment Ctr, Dept Neurol, New Taipei 23561, Taiwan

[7] Taipei Med Univ, Taipei Neurosci Inst, New Taipei 23561, Taiwan

[8] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 11031, Taiwan

[9] Taipei Med Univ, Taipei Med Univ Hosp, Dept Otolaryngol, Taipei 11031, Taiwan

[10] Taipei Med Univ, Coll Med, Sch Med, Dept Urol, Taipei 11031, Taiwan

[11] Taipei Med Univ, Wan Fang Hosp, Dept Med Educ & Res, Taipei 11696, Taiwan

[12] Fu Jen Catholic Univ, Cardinal Tien Hosp, Coll Med, Sch Med,Dept Pathol, New Taipei 23148, Taiwan

[13] Taipei Med Univ Hosp, Dept Radiat Oncol, Taipei 11031, Taiwan

[14] Taipei Med Univ, Shuang Ho Hosp, Dept Chest Med, New Taipei 23561, Taiwan

[15] Taipei Med Univ, Shuang Ho Hosp, Dept Internal Med, Div Nephrol, New Taipei 23561, Taiwan

[16] Taipei Med Univ, Shuang Ho Hosp, Dept Urol, New Taipei 23561, Taiwan

[17] Taipei Med Univ, Wan Fang Hosp, Cell Physiol & Mol Image Res Ctr, Taipei 11696, Taiwan

关键词: Castration-resistant prostate cancer;    CRPC;    Docetaxel;    POLQ;    CDK1;   

DOI  :  10.1016/j.bbadis.2020.165954

来源: Elsevier

【 摘 要 】

Objective: Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients. Methods: We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays. Results: We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells. Conclusion: Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.

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