Malonyl-CoA promotes prostate cancer progression and resistance to enzalutamide via regulating lipogenesis and malonylating Ran

Metabolic reprograming companied with alterations of multiple metabolites has been characterized as a hallmark of malignancy. However, the roles of metabolites in metabolism reprogramming, carcinogenesis and drug resistance are largely unclear. Malonyl-CoA, as a key metabolite, is not only the building block for de novo FAs synthesis, but also a critical metabolic switcher to mediates flux control over mitochondrial FAs b-oxidation in cellular. But little is known about the levels and potential roles of malonyl-CoA in malignancy and drug resistance, especially in those characterized by abnormal lipid metabolism, such as prostate cancer (PCa). Here, we showed the levels of malonyl-CoA was increased in PCa, especially in castration resistant prostate cancer (CRPC), mainly because that the deletion of MLYCD expression repressed the conversion of malonyl-CoA to acetyl-CoA. The abnormal accumulation of malonyl-CoA promoted lipogenesis and reprogramed multiple metabolism (including lipid metabolism, glucose metabolism and amino acid metabolism), sustaining cellular homeostasis to contribute to PCa progression. Restoration of MLYCD expression activated PREK-mediated unfolded protein reaction (UPR) via consuming Malonyl-CoA. Importantly, we also found that malonyl-CoA as a donor of malonylation, promoted lysine malonylation in PCa. We identified that malonyl-CoA promoted Ran K141 malonylation, thereby increasing its activity and enhancing AR nuclear translocation and transcriptional activity, finally contributing to PCa development and resistance to antiandrogens. These findings highlighted the previously unrecognized role and function of MLYCD-mediated malonyl-CoA in PCa progression via the canonical pathway (metabolic reprogramming) and the non canonical pathway (malonylated Ran K141), systematically revealing that a mechanism that might be a potentially reliable therapeutic target for advanced PCa.