Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking.

Guang-Zhi Jin,Guanzhen Yu,Weiwei Yang,Siyao Wang,Weiping Zhou,Shengxian Yuan,Siyang Wu,Wen-Ming Cong,Xueyuan Wu,Yajuan Zhang,Xiongjun Wang,Hong Gao,Heather Christofk

doi:10.1371/journal.pbio.2006483

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.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is the sixth most prevalent cancer and the third most frequent cause of cancer-related death [1]
The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Immunohistochemical analyses of human HCC tumors indicate that low forkhead box protein J2 (FOXJ2) and Phosphoglucomutase 1 (PGM1) expression correlates with the malignancy and poor progression of human HCC. These results suggest that the activation of residual PGM1 may impair HCC development through switching glycolysis to glycogenesis

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is the sixth most prevalent cancer and the third most frequent cause of cancer-related death [1]. Due to the rapid progression of HCC, most HCC patients are diagnosed at advanced stage, the 5-year survival rate of advanced HCC patients is as low as 25% to 39%, and the recurrence rate is approximately 80% [2]. The interaction between KIAA1199 and glycogen phosphorylase kinase β-subunit (PHKB) or glycogen phosphorylase brain form (PYGB) can regulate glycogen breakdown to promote the survival of HCC cells under serum-free conditions [8]. These results strongly suggest the important role of deregulated metabolism in HCC development. How these metabolic pathways are altered and how these alterations contribute to the malignancy of HCC remain largely unknown

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