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Nat Commun. 2018 Oct 26;9(1):4468. doi: 10.1038/s41467-018-06812-y.

Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis.

Wei Z1, Song J2,3, Wang G2,3, Cui X2,3, Zheng J1, Tang Y1, Chen X1, Li J1, Cui L4,5, Liu CY6,7, Yu W8,9.

Author information

1
State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
2
Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
3
Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.
4
Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. cuilong@xinhuamed.com.cn.
5
Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China. cuilong@xinhuamed.com.cn.
6
Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. liuchenying@xinhuamed.com.cn.
7
Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China. liuchenying@xinhuamed.com.cn.
8
State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200438, China. yuw@fudan.edu.cn.
9
Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. yuw@fudan.edu.cn.

Abstract

The conversion of serine and glycine that is accomplished by serine hydroxymethyltransferase 2 (SHMT2) in mitochondria is significantly upregulated in various cancers to support cancer cell proliferation. In this study, we observed that SHMT2 is acetylated at K95 in colorectal cancer (CRC) cells. SIRT3, the major deacetylase in mitochondria, is responsible for SHMT2 deacetylation. SHMT2-K95-Ac disrupts its functional tetramer structure and inhibits its enzymatic activity. SHMT2-K95-Ac also promotes its degradation via the K63-ubiquitin-lysosome pathway in a glucose-dependent manner. TRIM21 acts as an E3 ubiquitin ligase for SHMT2. SHMT2-K95-Ac decreases CRC cell proliferation and tumor growth in vivo through attenuation of serine consumption and reduction in NADPH levels. Finally, SHMT2-K95-Ac is significantly decreased in human CRC samples and is inversely associated with increased SIRT3 expression, which is correlated with poorer postoperative overall survival. Our study reveals the unknown mechanism of SHMT2 regulation by acetylation which is involved in colorectal carcinogenesis.

PMID:
30367038
PMCID:
PMC6203763
DOI:
10.1038/s41467-018-06812-y
[Indexed for MEDLINE]
Free PMC Article

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