SQLE-mediated squalene metabolism is critical for mitochondrial biogenesis and tumor development in K-ras-driven cancer

Abstract Despite the widely recognition of K-ras oncogenic role, the underlying biochemical pathways and metabolic regulation that promote cancer development remain to be characterized. Here we show that SQLE, a key enzyme in cholesterol synthesis, is upregulated by K-ras and its expression levels are closely correlated with poor prognosis of pancreatic cancer patients. Mechanistically, SQLE is essential for the timely metabolic removal of the endogenous squalene, which at high concentration inhibits PGC-1α-mediate mitochondrial biogenesis via promoting the formation of an aberrant Sp1-TFAP2E promoter complex and thus hindering TFAP2E’s expression, leading to a major inhibition of mitochondrial biogenesis and suppression of respiratory function. This regulatory mechanism is independent of cholesterol synthesis. Genetic knockdown of SQLE caused a high accumulation of squalene in pancreatic cancer cells with K-ras mutation, and almost completely abolished tumor growth. Administration of squalene also inhibits tumor growth in vivo. Our study has revealed a previously unrecognized role of SQLE in K-ras-driven cancer, and also identifies the SQLE/TFAP2E/PGC-1α axis as a novel target for intervention of pancreatic cancer metabolism for therapeutic purpose.