Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex

Dongnan Ping; Xiaofan Pu; Guoping Ding; Chaolei Zhang; Junbin Jin; Chengjie Xu; Jiazheng Liu; Shengnan Jia; Liping Cao

doi:10.1016/j.bbagrm.2023.194941

Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex

Biochim Biophys Acta Gene Regul Mech. 2023 Jun;1866(2):194941. doi: 10.1016/j.bbagrm.2023.194941. Epub 2023 May 3.

Authors

Dongnan Ping¹, Xiaofan Pu¹, Guoping Ding¹, Chaolei Zhang¹, Junbin Jin¹, Chengjie Xu¹, Jiazheng Liu², Shengnan Jia³, Liping Cao⁴

Affiliations

¹ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3, Qingchun Road, Hangzhou, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macao.
³ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3, Qingchun Road, Hangzhou, China; Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China. Electronic address: jiashengnan8180@zju.edu.cn.
⁴ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3, Qingchun Road, Hangzhou, China; Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China. Electronic address: caolipingzju@zju.edu.cn.

PMID: 37146713
DOI: 10.1016/j.bbagrm.2023.194941

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. As a tumor inhibitor, the specific tumor suppressor mechanism of Sirtuin4(SIRT4) in PDAC remains elusive. In this study, SIRT4 was found to inhibit PDAC by impacting mitochondrial homeostasis. SIRT4 deacetylated lysine 547 of SEL1L and increased the protein level of an E3 ubiquitin ligase HRD1. As a central member of ER-associated protein degradation (ERAD), HRD1-SEL1L complex is recently reported to regulate the mitochondria, though the mechanism is not fully delineated. Here, we found the increase in SEL1L-HRD1 complex decreased the stability of a mitochondrial protein, ALKBH1. Downregulation of ALKBH1 subsequently blocked the transcription of mitochondrial DNA-coded genes, and resulted in mitochondrial damage. Lastly, a putative SIRT4 stimulator, Entinostat, was identified, which upregulated the expression of SIRT4 and effectively inhibited pancreatic cancer in vivo and in vitro.

Keywords: ALKBH1; HRD1-SEL1L; Mitochondrial function; Pancreatic cancer; SIRT4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AlkB Enzymes
AlkB Homolog 1, Histone H2a Dioxygenase
Endoplasmic Reticulum-Associated Degradation*
Homeostasis
Humans
Mitochondria
Pancreatic Neoplasms* / genetics
Proteins

Substances

AlkB Enzymes
ALKBH1 protein, human
AlkB Homolog 1, Histone H2a Dioxygenase
SEL1L protein, human
Proteins