Deciphering the Role of LRH-1 in Liver Intermediary Metabolism and Cancer

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Gaining insight into the molecular pathways involved in the development of HCC is hence a prerequisite to design and develop novel and effective therapeutic strategies. Metabolic reprogramming is a universal feature of tumor cells and is characterized by increased glycolysis and diminished oxidative phosphorylation, a phenomenon known as the Warburg effect. More recently, it has become evident that tumor cells heavily rely on gluta-mine metabolism to compensate for the Warburg effect and to replenish the tricarboxylic acid (TCA) cycle. However, the molecular mechanisms by which glutamine supports tumor cell metabolism remain largely unexplored. In this thesis, I have established the role of the nuclear receptor LRH-1 as a key regulator in the process of hepatic tumorigenesis. I observed that LRH-1 promotes DEN-induced hepatocellular carcinogenesis (HCC). I demonstrated that LRH-1 facilitates the production of NADPH from glutamine by favoring a non-canonical glutamine pathway that optimizes reductive biosynthesis. Importantly, chronic and acute disrup-tion of LRH-1 also impaired glutamine-induced anaplerosis and α-KG availability, ultimately leading to im-paired mTORC1 signaling to block cell proliferation. Moreover, LRH-1 also coordinates glutamine-dependent asparagine synthesis to protect tumor cell from apoptosis induced by glutamine depletion itself. As a result, gain-of-function of LRH-1 sustained aspar-agine homeostasis upon glutamine-deprivation to promote cell survival. Collectively, these studies unveiled an unexpected role of LRH-1 in cancer intermediary metabolism, and warranted further studies on pharma-cological inhibition of LRH-1 to interfere with hepatocellular carcinogenesis.

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