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
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.
