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

Abstract

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.

• Authors: Chia-Hao Kuei, Hui-Yu Lin, Min-Hsuan Lin, Hsun-Hua Lee, Che-Hsuan Lin, Wei-Jiunn Lee, Yen-Lin Chen, Long-Sheng Lu, Jing-Quan Zheng, Ruei-Chen Hung, Hui-Wen Chiu, Kuan-Chou Chen, Yuan-Feng Lin
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1866 Issue 12 Pg. 165954 (12 01 2020) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 32877750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• RNA, Messenger
• Docetaxel
• DNA polymerase theta
• DNA-Directed DNA Polymerase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• DNA-Directed DNA Polymerase (genetics, metabolism)
• Docetaxel (pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• PC-3 Cells
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• RNA, Messenger (drug effects, genetics, metabolism)
• Tumor Cells, Cultured