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SIRT3 suppression resulting from the enhanced β-catenin signaling drives glycolysis and promotes hypoxia-induced cell

Rong Ma1,2, Qing-Yuan Gao2, Zhi-Teng Chen2

  • 1Department of Infectious Diseases, The First Affiliated Hospital of Chengdu Medical College, Chengdu, PRC.

Cell Cycle (Georgetown, Tex.)
|April 16, 2024
PubMed
Summary

Sirtuin 3 (SIRT3) inhibits hepatocellular carcinoma (HCC) cell growth by modulating mitochondrial respiration and glycolysis. Reduced SIRT3 expression in HCC is linked to β-catenin, suggesting a new therapeutic target for liver cancer.

Keywords:
Hepatocellular carcinomaSirtuins 3glycolysismitochondriaβ-catenin

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Area of Science:

  • Mitochondrial biology
  • Cancer research
  • Molecular oncology

Background:

  • Sirtuin 3 (SIRT3) is a mitochondrial sirtuin with poorly understood roles in hepatocellular carcinoma (HCC) and mitochondrial respiration.
  • SIRT3 expression is reduced in HCC tissues and under hypoxic conditions, a common feature in tumors.

Purpose of the Study:

  • To elucidate the mechanisms by which SIRT3 inhibits HCC development and affects mitochondrial function.
  • To investigate the regulation of SIRT3 expression by β-catenin in hypoxic HCC cells.

Main Methods:

  • Assessed SIRT3 levels in HCC tissues and Huh7 cells under hypoxia.
  • Investigated SIRT3's effects on proliferation, glycolysis, mitochondrial respiration, mitophagy, and biogenesis in Huh7 cells.
  • Explored β-catenin's role in regulating SIRT3 expression.

Main Results:

  • SIRT3 expression was reduced in HCC tissues and hypoxic Huh7 cells.
  • Forced SIRT3 expression inhibited HCC cell growth, decreased glycolysis (ECAR), and increased mitochondrial respiration (OCAR).
  • SIRT3 modulated key metabolic enzymes, enhanced mitophagy, promoted mitochondrial biogenesis, and its expression was inversely regulated by β-catenin.

Conclusions:

  • SIRT3 suppresses HCC cell proliferation by reprogramming cellular metabolism, enhancing mitochondrial function, and promoting mitophagy.
  • β-catenin downregulates SIRT3 expression under hypoxia, identifying a novel regulatory pathway in HCC progression.