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

Yan Li*, Shuhai LIN, Lei Li, Zhi Tang, Yumin Hu, Xiaojiao Ban, Tingting Zeng, Ying Zhou, Yinghui Zhu, Song Gao, Wen Deng, Xiaoshi Zhang, Dan Xie, Yunfei Yuan, Peng Huang, Jinjun Li, Zongwei CAI, Xin Yuan Guan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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 for 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 ¼ 0.027). PDSS2 downregulation was a prognostic factor independent of T status and stage (P ¼ 0.028). Downregulation of CoQ10 was significantly correlated with downregulation of PDSS2 in HCC tumor tissues (R ¼ 0.414; P < 0.001). Of the six different splicing isoforms of PDSS2, the five variants other than 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 MIHA immortalized human liver cell line. 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. Significance: Downregulation of PDSS2 is a driving factor in hepatocellular carcinoma tumorigenesis.

Original languageEnglish
Pages (from-to)4471-4481
Number of pages11
JournalCancer Research
Volume78
Issue number16
DOIs
Publication statusPublished - 15 Aug 2018

Scopus Subject Areas

  • Oncology
  • Cancer Research

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