Paraspeckles-Mediated Control of Cancer Metabolism by Nutrient-mTORC1 Signaling

Paraspeckles are distinct nuclear bodies formed by polymerization of the lncRNA NEAT1 with the RNA-binding proteins NONO and SFPQ. Despite recent advances in understanding the biogenesis and structural organization of paraspeckles, their function and regulation in response to changing cellular environments remain poorly understood. Herein we report identification of NEAT1 as a transcriptional target of mTORC1. Upon oncogenic activation, mTORC1 binds to NEAT1 promoter, thereby repressing NEAT1 transcription and suppressing paraspeckle biogenesis in response to nutrient and mitogenic signals. Functionally, mTORC1 suppression of paraspeckle formation liberates NONO, which in turn, binds to U5 spliceosome and enhances splicing of key glycolytic genes and aerobic glycolysis, promoting cancer cell growth in vitro and tumor development in vivo. Furthermore, this paraspeckle-mediated mechanism is important for the anticancer action of rapamycin/temsirolimus. Collectively, these findings reveal a function of nuclear paraspeckles in controlling cancer metabolism and mediating the anticancer responses of mTORC1-targeted agents.