Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells

• Published in: Cell death & disease Vol. 1; no. 12; p. e105
• Main Authors: Bhatnagar, N, Li, X, Padi, S K R, Zhang, Q, Tang, M-S, Guo, B
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 01.12.2010; Nature Publishing Group
• Subjects: Animals; Antimetabolites, Antineoplastic - therapeutic use; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Apoptosis Regulatory Proteins - physiology; Azacitidine - analogs & derivatives; Azacitidine - therapeutic use; Cell Line, Tumor; DNA Methylation; DNA Modification Methylases - antagonists & inhibitors; Down-Regulation; Drug Resistance, Neoplasm - genetics; E2F6 Transcription Factor - genetics; E2F6 Transcription Factor - metabolism; E2F6 Transcription Factor - physiology; Humans; Male; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Original; Promoter Regions, Genetic; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; miR-31; apoptosis; prostate cancer; miR-205; Bcl-w; E2F6
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2010.85

Advanced prostate cancers are known to acquire not only invasive capabilities but also significant resistance to chemotherapy-induced apoptosis. To understand how microRNAs (miRNAs) may contribute to prostate cancer resistance to apoptosis, we compared microRNA expression profiles of a benign prostate cancer cell line WPE1-NA22 and a highly malignant WPE1-NB26 cell line (derived from a common lineage). We found that miR-205 and miR-31 are significantly downregulated in WPE1-NB26 cells, as well as in other cell lines representing advanced-stage prostate cancers. Antiapoptotic genes BCL2L2 (encoding Bcl-w) and E2F6 are identified as the targets of miR-205 and miR-31, respectively. By downregulating Bcl-w and E2F6, miR-205 and miR-31 promote chemotherapeutic agents-induced apoptosis in prostate cancer cells. The promoter region of the miR-205 gene was cloned and was found to be hypermethylated in cell lines derived from advanced prostate cancers, contributing to the downregulation of the gene. Treatment with DNA methylation inhibitor 5-aza-2'-deoxycytidine induced miR-205 expression, downregulated Bcl-w, and sensitized prostate cancer cells to chemotherapy-induced apoptosis. Thus, downregulation of miR-205 and miR-31 has an important role in apoptosis resistance in advanced prostate cancer.