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UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis

Liang Zhao1, Min Kang1, Xiaomeng Liu1

  • 1Department of Hepatobiliary Surgery and Oncology, The First Affiliated Hospital of Guangxi Medical University, No 6 Shuangyong Road, Nanning, 530021, Guangxi, People's Republic of China.

Journal of Experimental & Clinical Cancer Research : CR
|November 24, 2022
PubMed
Abstract

Insights

UBR7, a ubiquitin ligase, suppresses hepatocellular carcinoma (HCC) by inhibiting glycolysis. Loss of UBR7 promotes HCC, highlighting its therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Glycolysis is a key target for cancer therapy, especially for cancers with limited treatment options.
  • The ubiquitin-proteasome system, involving E3 ligases, regulates protein turnover.
  • UBR7, an understudied E3 ligase, plays a role in glycolysis and HCC tumorigenesis via histone modification.

Purpose of the Study:

  • To investigate the role of UBR7 in regulating glycolysis and hepatocellular carcinoma (HCC) progression.
  • To identify epigenetic regulators of lactic acid metabolism in HCC.

Main Methods:

  • High-throughput RNAi screening was employed to identify epigenetic candidates.
  • Investigated the mechanism of UBR7's regulation of glycolysis and HCC tumorigenesis.
  • Analyzed the impact of UBR7 on histone H2B monoubiquitination (H2BK120ub) and downstream signaling pathways.

Main Results:

  • UBR7 loss promotes HCC tumorigenesis in vitro and in vivo.
  • UBR7 inhibits glycolysis by suppressing HK2 expression via the Keap1/Nrf2/Bach1 axis.
  • UBR7 regulates H2BK120ub, affecting Keap1 expression and downstream signaling.
  • ALKBH5 regulates UBR7 expression in an m6A-dependent manner.

Conclusions:

  • UBR7 is a critical negative regulator of aerobic glycolysis and HCC tumorigenesis.
  • The UBR7-regulated Keap1/Nrf2/Bach1/HK2 axis is crucial for HCC progression.
  • UBR7 represents a potential therapeutic target for HCC treatment.
Keywords:
GlycolysisHepatocellular carcinomaKeap1-Nrf2-Bach1 signalingMonoubiquitinationUBR7

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