Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

PLoS Biol. 2018 Oct 18;16(10):e2006483. doi: 10.1371/journal.pbio.2006483. eCollection 2018 Oct.

Abstract

Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Down-Regulation
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism*
  • Glycolysis
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Phosphoglucomutase / deficiency
  • Phosphoglucomutase / genetics
  • Phosphoglucomutase / metabolism*
  • Prognosis
  • Promoter Regions, Genetic
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • CNBP protein, human
  • FOXJ2 protein, human
  • Forkhead Transcription Factors
  • RNA-Binding Proteins
  • PGM1 protein, human
  • Phosphoglucomutase
  • Glucose

Grants and funding

Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB19000000). To WY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number 31471324). To WY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number 31422034). To WY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Thousand Talents Plan-Youth. To WY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number 81572856). To GY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number 81472769). To GJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number 81201937). To GJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number 81521091). To WC. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.