PDSS2 deficiency induces hepatocarcinogenesis by decreasing mitochondrial respiration and reprogramming glucose metabolism

Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is one of the hallmarks of cancer development. Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Here we investigated the role of a key factor in CoQ10 synthesis, prenyldiphosphate synthase subunit 2 (PDSS2), in hepatocellular carcinoma (HCC) tumorigenesis. PDSS2 was frequently downregulated in HCC tissues and was significantly associated with poorer HCC prognosis (P=0.027). PDSS2 downregulation was an independent prognostic factor independent of T status and staging (P=0.028). Downregulation of CoQ10 significantly correlated with downregulation of PDSS2 in HCC tumor tissues (R=0.414, P<0.001). Six different splicing isoforms of PDSS2 and five variants, except full-length PDSS2, showed loss of function in HCC. Reintroduction of full-length PDSS2 into HCC cells increased CoQ10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Reintroduction of PDSS2 also inhibited foci formation, colony formation in soft agar, and tumor formation in nude mice. Knockdown of PDSS2 induced chromosomal instability in the immortalized human liver cell line MIHA. Furthermore, knockdown of PDSS2 in MIHA induced malignant transformation. Overall, our findings indicate that PDSS2 deficiency might be a novel driving factor in HCC development.

https://ift.tt/2z4RniF