Long non-coding RNA SNHG6 couples cholesterol sensing with mTORC1 activation in hepatocellular carcinoma

Menée à l'aide de lignées cellulaires et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel le long ARN non codant SNHG6, en augmentant l'activation du complexe mTORC1 dépendante du cholestérol, favorise la progression d'une stéatose hépatique non alcoolique vers un carcinome hépatocellulaire

Résumé en anglais

Cholesterol contributes to the structural basis of biological membranes and functions as a signaling molecule, whose dysregulation has been associated with various human diseases. Here, we report that the long non-coding RNA (lncRNA) SNHG6 increases progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) by modulating cholesterol-induced mTORC1 activation. Mechanistically, cholesterol binds ER-anchored FAF2 protein to promote the formation of a SNHG6–FAF2–mTOR complex. As a putative cholesterol effector, SNHG6 enhances cholesterol-dependent mTORC1 lysosomal recruitment and activation via enhancing FAF2–mTOR interaction at ER–lysosome contacts, thereby coordinating mTORC1 kinase cascade activation with cellular cholesterol biosynthesis in a self-amplified cycle to accelerate cholesterol-driven NAFLD–HCC development. Notably, loss of SNHG6 inhibits mTORC1 signaling and impairs growth of patient-derived xenograft liver cancer tumors, identifyifng SNHG6 as a potential target for liver cancer treatment. Together, our findings illustrate the crucial role of organelle-associated lncRNA in organelle communication, nutrient sensing, and kinase cascades.