SNHG6 Couples Cholesterol Sensing With MTORC1 Activation In Liver Cancer

Cholesterol,an essential lipid for eukaryotic cells,is involved in multiple cellular processes,whose dysregulation has been associated with various human diseases.It has been reported that cholesterol is dynamically transported and distributed in several organelles by membrane contacts,to maintain intracellular metabolic homeostasis.However,the function of cholesterol-induced organelle contacts in signal and metabolic regulation remains to be elucidated.Here,we found that lncRNA SNHG6 was distributed to the cholesterol-induced ER-lysosome contact sites to promote mTORC1 activation in liver cancer,which contributed to the proliferation and poor survival.SNHG6-pulldown MS analysis was performed to search for the proteins that bind SNHG6.Among them,the cholesterol-mediated interaction between SNHG6 with FAF2 or mTOR was observed.Subsequently,the binding region of SNHG6 to FAF2/mTOR and its localization on the organelles were explored.Mechanically,cholesterol driven the localization of SNHG6 on ER-lysosome contact sites by the assembly of the SNHG6-FAF2-mTOR complex.Indeed,cholesterol specifically bound to FAF2-P354 and in turn changed its conformation,which enabled FAF2 to interact with SNHG6-mTOR complex,which resulted in the mTORC1 lysosomal recruitment and activation,accelerating the de novo synthesis of cholesterol.By constructing several mice models,we found that SNHG6 coordinated mTORC1 kinase cascade activation with cellular cholesterol biosynthesis in a self-amplified cycle to accelerate cholesterol-driven NAFLD-HCC development.Moreover,loss of SNHG6 inhibits mTORC1 signaling and impairs growth of patient-derived xenograft liver cancer tumors,identifying 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.