Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability

Hao-Lian Wang, Yan Chen, Yun-Qian Wang, En-Wei Tao, Juan Tan, Qian-Qian Liu, Chun-Min Li, Xue-Mei Tong, Qin-Yan Gao, Jie Hong, Ying-Xuan Chen () and Jing-Yuan Fang
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Hao-Lian Wang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Yan Chen: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Yun-Qian Wang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
En-Wei Tao: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Juan Tan: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Qian-Qian Liu: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Chun-Min Li: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Xue-Mei Tong: Shanghai Jiao Tong University School of Medicine
Qin-Yan Gao: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Jie Hong: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Ying-Xuan Chen: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Jing-Yuan Fang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract In our previous study, we reported that sirtuin5 (SIRT5), a member of the NAD+-dependent class III histone deacetylase family, is highly expressed in colorectal cancer (CRC). Herein we show that SIRT5 knockdown impairs the production of ribose-5-phosphate, which is essential for nucleotide synthesis, resulting in continuous and irreparable DNA damage and consequently leading to cell cycle arrest and enhanced apoptosis in CRC cells. These SIRT5 silencing-induced effects can be reversed by nucleoside supplementation. Mechanistically, SIRT5 activates transketolase (TKT), a key enzyme in the non-oxidative pentose phosphate pathway, in a demalonylation-dependent manner. Furthermore, TKT is essential for SIRT5-induced malignant phenotypes of CRC both in vivo and in vitro. Altogether, SIRT5 silencing induces DNA damage in CRC via post-translational modifications and inhibits tumor growth, suggesting that SIRT5 can serve as a promising target for CRC treatment.

Date: 2022
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DOI: 10.1038/s41467-022-33903-8

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