2. Academic Validation
  3. SIRT3 inhibits gallbladder cancer by induction of AKT-dependent ferroptosis and blockade of epithelial-mesenchymal transition

SIRT3 inhibits gallbladder cancer by induction of AKT-dependent ferroptosis and blockade of epithelial-mesenchymal transition

  • Cancer Lett. 2021 Jul 10;510:93-104. doi: 10.1016/j.canlet.2021.04.007.
Liguo Liu 1,  Yang Li 1,  Dongyan Cao 2,  Shimei Qiu 3,  Yongsheng Li 1,  Chengkai Jiang 1,  Rui Bian 1,  Yang Yang 1,  Lin Li 1,  Xuechuan Li 1,  Ziyi Wang 1,  Zheng Ju 2,  Yijian Zhang 4,  Yingbin Liu 5
Affiliations

Affiliations

  • 1 Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
  • 2 Novogene Bioinformatics Institute, Beijing, 100015, China.
  • 3 Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
  • 4 Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China. Electronic address: zhangyijian@xinhuamed.com.cn.
  • 5 Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China. Electronic address: laoniulyb@shsmu.edu.cn.
PMID: 33872694 DOI: 10.1016/j.canlet.2021.04.007
Abstract

Dysfunction of Sirtuin 3 (SIRT3), an NAD+-dependent histone deacetylase, impairs varied mitochondrial metabolic pathways in human Cancer. Here, we explored suppressive activity of SIRT3 in the progression of gallbladder Cancer (GBC). Expression levels of SIRT3 in patients with GBC were lower than those in the adjacent normal tissue. In addition, decreased expression of SIRT3 in these patients was correlated with poor overall survival. Knockdown of SIRT3 gene in GBC cell lines induced mitochondrial respiration and energy metabolism, but inhibited oxidative ROS. Silence of SIRT3 gene also suppressed AKT-dependent Ferroptosis, an iron-dependent and lipid peroxide-mediated cell death. Blockade of Akt activity in sh-SIRT3 cells induced ACSL4 expression that drives Ferroptosis, and inhibited epithelial-mesenchymal (EMT) markers and invasive activity. In contrast, overexpression of SIRT3 led to the opposite effects on Mitochondrial Metabolism and EMT. Finally, transplantation of sh-SIRT3 cells in nude mice resulted in rapid tumor growth and larger tumors that expressed lower E-cadherin and lipid peroxide 4-hydroxynonenal (4-HNE) than those observed in control tumors. Collectively, our studies indicate that SIRT3 functions to inhibit AKT-dependent Mitochondrial Metabolism and EMT, leading to Ferroptosis and tumor suppression.

Keywords

Cancer progression; Ferroptosis; GBC; Mitochondrial metabolism; SIRT3.

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