mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma
Description
Hepatocellular Carcinoma (HCC) undergoes metabolic reprogramming glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the ‘Warburg Effect’ that critically supports rapid cancer cell growth, survival and invasion. mTOR pathway is a central controller of cell growth, a driver of HCC and a key regulator of ‘Warburg Effect’, but the underlying mechanism remains poorly defined. The aim of this study is to understand the mechanism and significance of mTOR regulation of aerobic glycolysis in HCC. In this manuscript, we report that mTOR, regulates the long non-coding RNA (lncRNA) transcriptome in HCC cells. One of the mTOR target lncRNAs, NEAT1, is significantly down-regulated in HCC, which is correlated with poor prognosis. NEAT1 is the organizer of nuclear paraspeckles that sequester NONO/SFPQ. We show that mTORC1 suppresses NEAT1 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. These series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production and HCC growth in vitro and in vivo. Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus. These findings reveal a major molecular mechanism by which mTOR pathway promotes ‘Warburg Effect’, which is important for the metabolism, growth and development of HCC, and anticancer response of mTOR-targeted therapy.