Acsm1 And Acsm3 Regulate Fatty Acid Oxidation In Prostate Cancer To Promote Growth And Protect Against Oxidative Stress.

Prostate tumours are highly reliant on lipids for growth and survival. Emerging evidence suggests that the androgen receptor (AR) is a major regulator of lipid metabolism in prostate cancer (PCa), but the molecular mechanisms underlying such regulation are largely unknown. By integrating cistromic and transcriptomic data, we identified Acyl-CoA Synthetase Medium Chain Family Members 1 and 3 (ACSM1 and ACSM3) as putative new AR-regulated genes in prostate cancer. These factors are thought to function to activate fatty acids for their utilisation in energy production via mitochondrial beta-oxidation. AR regulation was validated by demonstrating modulation of ACSM1 and ACSM3 by androgen and anti-androgen treatment and confirming direct binding of AR to proximal cis-regulatory elements by chromatin immunoprecipitation (ChIP). ACSM1 and ACSM3 are upregulated in prostate tumours compared to non-malignant prostate tissues and are expressed more highly in prostate cancer than other cancer types. We subsequently applied metabolomics, lipidomics and functional assays to decipher the roles of ACSM1 and ACSM3 in prostate cancer cells. Knockdown of ACSM1 and ACSM3 in PCa cells resulted in growth arrest and ATP depletion, supporting a key role for both factors in energy production from fatty acids. Furthermore, lipidomic analysis of cells showed that poly-unsaturated fatty acids accumulate in response to loss of ACSM1 and ACSM3. Metabolomics revealed that cells adapt to loss of ACSM1 and ACSM3 by switching to a glycolytic phenotype. The metabolic dysregulation induced by knockdown of ACSM1 and ACSM3 caused mitochondrial oxidative stress and subsequent lipid peroxidation, eventually resulting in cell death. Accumulation of mitochondrial reactive oxygen species was abrogated by ferrostatin-1 (an iron chelator), suggesting that cell death was due to an iron-dependent form of apoptosis termed ferroptosis. Supporting this concept, over-expression of ACSM1 and ACSM3 elicited resistance to the ferroptosis inducers Erastin and ML210. Our study has revealed a novel mechanism by which AR regulates lipid metabolism in prostate cancer cells. Importantly, the critical role of ACSM1 and ACSM3 as key regulators of growth and protectors against ferroptosis emphasises their potential as novel therapeutic targets Citation Format: Raj Kumar Shrestha, Scott Townley, Adrienne Hanson, Marie Pickering, Zeyad D. Nassar, Chui Yan Mah, Mohammadreza A. Ghodsi, Andrew J. Hoy, Lake-Ee Quek, Wayne D. Tilley, Lisa M. Butler, Luke A. Selth. ACSM1 and ACSM3 regulate fatty acid oxidation in prostate cancer to promote growth and protect against oxidative stress [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-036.