A Long Noncoding RNA, GAS5 Can Be a Biomarker for Docetaxel Response in Castration Resistant Prostate Cancer

Abstract

While functional studies of long noncoding RNAs (lncRNAs) have mostly focused on how they influence disease diagnosis and prognosis, the pharmacogenomic relevance of lncRNAs remains largely unknown. Here, we test the hypothesis that the expression of a lncRNA, grow arrest-specific 5 (<i>GAS5</i>) can be a biomarker for docetaxel response in castration resistant prostate cancer (CRPC) using both prostate cancer (PCa) cell lines and CRPC patient datasets. Our results suggest that lower <i>GAS5</i> expression is associated with docetaxel resistance in both PCa cell lines and CRPC patients. Further experiments also suggest that <i>GAS5</i> is downregulated in docetaxel resistant CRPC cell lines, which reinforces its potential as a biomarker for docetaxel response. To examine the underlying biological mechanisms, we transiently knockdown <i>GAS5</i> expression in PCa cell lines and then subject the cells to docetaxel treatment overtime. We did not observe a decrease in docetaxel induced growth inhibition or apoptosis in the siRNA treated cells. The findings suggest that there is no direct causal relationship between change in <i>GAS5</i> expression and docetaxel response. Subsequently, we explored the indirect regulation among <i>GAS5</i>, ATP binding cassette subfamily B member 1 (<i>ABCB1</i>), and docetaxel sensitivity. We showed that transient knockdown <i>GAS5</i> did not lead to significant changes in <i>ABCB1</i> expression. Therefore, we rule out the hypothesis that <i>GAS5</i> directly down regulate <i>ABCB1</i> that lead to docetaxel sensitivity. In conclusion, our work suggests that <i>GAS5</i> can serve as a predictive biomarker for docetaxel response in CRPC; however, the exact mechanism behind the observed correlation remain to be elucidated.