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Abstract
Androgen receptor (AR) plays a critical role in prostate cancer development and its progression. It has been well-documented that AR is a transcriptional activator. Recently, several studies have demonstrated that AR can also act as a transcriptional repressor. On the other hand, fatty acid metabolism is aberrantly elevated in prostate cancer. How AR regulates fatty acid metabolism is not completely understood. Some evidence has indicated that expression levels of Long-Chain Fatty Acyl-CoA synthetase 4 (ACSL4) have an inversed relationship with AR levels in prostate cancer. ACSL4 catalyzes the conversion of fatty acids to fatty acyl-CoA in fatty acid metabolism. It promotes castration-resistant prostate cancer growth and proliferation. In this study, we demonstrate that knockdown of AR gene increased mRNA and protein levels of ACSL4 in prostate cancer cells. Through ChIP-qPCR analysis, we show that AR protein bound to the ACSL4 promoter region. Our studies suggest a molecular mechanism that suppression of AR activity results in de-repression of ACSL4 expression, thus up-regulates the biosynthesis of fatty acyl-CoAs. AR-ACSL4 pathway may maintain the fatty acid metabolism to generate ATP in androgen depleted stage of prostate cancer cells. Our study provides a mechanism that AR repression leads to up-regulation of a downstream gene, which potentially sustained survival of prostate cancer cells to develop castration resistant prostate cancer. Therefore, the development of combination therapies that simultaneously targeting AR and ACSL4-regulated fatty acid metabolism may potentially inhibit the occurrence of castration resistant prostate cancer.