OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism

Abstract Background & Aims Mitochondrial dysfunction and subsequent metabolic deregulation are commonly observed in cancers including hepatocellular carcinoma (HCC). When mitochondrial function is impaired, reductive glutamine metabolism is a major cellular carbon source for de novo lipogenesis to support cancer cell growth. The underlying regulators of reductively metabolized glutamine in mitochondrial dysfunction are not completely understood in tumorigenesis including in HCC. Methods We systematically investigated the role of oxoglutarate dehydrogenase-like (OGDHL), one of the rate-limiting components of the key mitochondrial multi-enzyme OGDH complex (OGDHC), in the regulation of lipid metabolism in hepatoma cells and explored the underlying molecular mechanisms. Results Lower expression of OGDHL was associated with advanced tumor stage, significantly worse survival and more frequent tumor recurrence in three independent cohorts totaling 681 postoperative HCC patients. Promoter hypermethylation and DNA copy deletion of OGDHL were independently correlated with reduced OGDHL expression in HCC specimens. Additionally, OGDHL overexpression significantly inhibited the growth of hepatoma cells as mouse xenografts while knockdown of OGDHL promoted proliferation in hepatoma cells. Mechanistically, OGDHL downregulation upregulated the α-ketoglutarate (αKG):citrate ratio by reducing OGDHC activity, which subsequently drove reductive carboxylation (RC) of glutamine-derived αKG for lipogenesis via retrograde TCA cycling in hepatoma cells. Notably, silencing of OGDHL activated the mTORC1 signaling pathway in an α-KG-dependent manner, which in turn transcriptionally induced expression of SCD1 and FASN, thus, enhancing de novo lipogenesis. Meanwhile, metabolic reprogramming in OGDHL-negative hepatoma cells provided an abundant supply of NADPH and GSH to support the cellular antioxidant system. The reduction of reductive glutamine metabolism through OGDHL overexpression or through use of glutaminase inhibitors sensitized tumor cells to sorafenib, a molecular-targeted therapy for HCC. Conclusion Our findings established that silencing of OGDHL contributed to HCC development and survival by regulating glutamine metabolic pathways, and suggest OGDHL as a promising prognostic biomarker and therapeutic target for HCC.