NSD2 methylates AROS to promote SIRT1 activation and regulates fatty acid metabolism-mediated cancer radiotherapy

Xun Li; Da Song; Yaqi Chen; Changsheng Huang; Anyi Liu; Qi Wu; Xiaowei She; Kangdi Li; Kairui Wan; Chengxin Yu; Cheng Qiu; Lang Liu; Guihua Wang; Feng Xu; Jing Wang; Junbo Hu

Cell Reports (Oct 2023)

NSD2 methylates AROS to promote SIRT1 activation and regulates fatty acid metabolism-mediated cancer radiotherapy

Xun Li,
Da Song,
Yaqi Chen,
Changsheng Huang,
Anyi Liu,
Qi Wu,
Xiaowei She,
Kangdi Li,
Kairui Wan,
Chengxin Yu,
Cheng Qiu,
Lang Liu,
Guihua Wang,
Feng Xu,
Jing Wang,
Junbo Hu

Affiliations

Xun Li: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Da Song: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Yaqi Chen: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Changsheng Huang: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Anyi Liu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Qi Wu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Xiaowei She: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Kangdi Li: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Kairui Wan: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Chengxin Yu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Cheng Qiu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Lang Liu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Guihua Wang: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Feng Xu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Jing Wang: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China; Correspondence
Junbo Hu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China; Correspondence

Journal volume & issue: Vol. 42, no. 10
p. 113126

Abstract

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Summary: Fatty acid metabolism plays a critical role in both tumorigenesis and cancer radiotherapy. However, the regulatory mechanism of fatty acid metabolism has not been fully elucidated. NSD2, a histone methyltransferase that catalyzes di-methylation of histone H3 at lysine 36, has been shown to play an essential role in tumorigenesis and cancer progression. Here, we show that NSD2 promotes fatty acid oxidation (FAO) by methylating AROS (active regulator of SIRT1) at lysine 27, facilitating the physical interaction between AROS and SIRT1. The mutation of lysine 27 to arginine weakens the interaction between AROS and SIRT1 and impairs AROS-SIRT1-mediated FAO. Additionally, we examine the effect of NSD2 inhibition on radiotherapy efficacy and find an enhanced effectiveness of radiotherapy. Together, our findings identify a NSD2-dependent methylation regulation pattern of the AROS-SIRT1 axis, suggesting that NSD2 inhibition may be a potential adjunct for tumor radiotherapy.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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