HDAC8-dependent deacetylation of PKM2 directs nuclear localization and glycolysis to promote proliferation in hepatocellular carcinoma

Ruixue Zhang,Li Zhao,Chunhua Wu,Gang Huang,Huannan Meng,Xiang Zhou,Jiajin Li,Xiaoping Zhao,Jiani Lu,Mengqin Shen,Yumei Chen,Jianjun Liu

doi:10.1038/s41419-020-03212-3

Abstract

Pyruvate kinase M2 (PKM2) is not only a key rate-limiting enzyme that guides glycolysis, but also acts as a non-metabolic protein in regulating gene transcription. In recent years, a series of studies have confirmed that post-translational modification has become an important mechanism for regulating the function of PKM2, which in turn affects tumorigenesis. In this study, we found that K62 residues were deacetylated, which is related to the prognosis of HCC. Further studies indicate that HDAC8 binds and deacetylates the K62 residue of PKM2. Mechanistically, K62 deacetylation facilitate PKM2 transport into the nucleus and bind β-catenin, thereby promoting CCND1 gene transcription and cell cycle progression. In addition, the deacetylation of K62 affects the enzyme activity of PKM2 and the flux of glucose metabolism. Therefore, these results suggest that HDAC8 / PKM2 signaling may become a new target for the treatment of HCC.

Highlights

Liver cancer is predicted to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide in 2018, and its ranks fifth in terms of global cases and second in terms of deaths for males, and hepatocellular carcinoma (HCC) is the most prevalent form one[1]
We found that Histone deacetylase 8 (HDAC8) directly interacts with Pyruvate kinase M2 (PKM2) and deacetylates the conserved K62 residue in the cytoplasm, thereby regulating glucose metabolism and gene transcription
PKM2 plays an important role in tumor development and progression through the regulation of both metabolic and nonmetabolic pathways[26]

Summary

Introduction

Liver cancer is predicted to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide in 2018, and its ranks fifth in terms of global cases and second in terms of deaths for males, and hepatocellular carcinoma (HCC) is the most prevalent form one[1]. Previous study revealed PKM2 binds with several proteins that regulate glucose and lipid metabolism promote cell proliferation in HCC22. The K62 acetylation level of PKM2 in the tumor is lower than that of adjacent tissues, and it is accompanied by rapid cell proliferation (Fig. 1A).

Results

Conclusion