Deacetylation of Serine Hydroxymethyl-transferase 2 by SIRT3 Promotes Colorectal Carcinogenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Oct 28

PMID 30367038

Citations 92

Authors

Zhen Wei

Jinglue Song

Guanghui Wang

Ximao Cui

Jun Zheng

Yunlan Tang

Xinyuan Chen

Jixi Li

Long Cui

Chen-Ying Liu

Wei Yu

Affiliations

Soon will be listed here.

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.

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