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

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. SI...

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Autores principales: Wei, Zhen, Song, Jinglue, Wang, Guanghui, Cui, Ximao, Zheng, Jun, Tang, Yunlan, Chen, Xinyuan, Li, Jixi, Cui, Long, Liu, Chen-Ying, Yu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203763/
https://www.ncbi.nlm.nih.gov/pubmed/30367038
http://dx.doi.org/10.1038/s41467-018-06812-y
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author Wei, Zhen
Song, Jinglue
Wang, Guanghui
Cui, Ximao
Zheng, Jun
Tang, Yunlan
Chen, Xinyuan
Li, Jixi
Cui, Long
Liu, Chen-Ying
Yu, Wei
author_facet Wei, Zhen
Song, Jinglue
Wang, Guanghui
Cui, Ximao
Zheng, Jun
Tang, Yunlan
Chen, Xinyuan
Li, Jixi
Cui, Long
Liu, Chen-Ying
Yu, Wei
author_sort Wei, Zhen
collection PubMed
description 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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spelling pubmed-62037632018-10-29 Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis Wei, Zhen Song, Jinglue Wang, Guanghui Cui, Ximao Zheng, Jun Tang, Yunlan Chen, Xinyuan Li, Jixi Cui, Long Liu, Chen-Ying Yu, Wei Nat Commun Article 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. Nature Publishing Group UK 2018-10-26 /pmc/articles/PMC6203763/ /pubmed/30367038 http://dx.doi.org/10.1038/s41467-018-06812-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wei, Zhen
Song, Jinglue
Wang, Guanghui
Cui, Ximao
Zheng, Jun
Tang, Yunlan
Chen, Xinyuan
Li, Jixi
Cui, Long
Liu, Chen-Ying
Yu, Wei
Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
title Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
title_full Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
title_fullStr Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
title_full_unstemmed Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
title_short Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
title_sort deacetylation of serine hydroxymethyl-transferase 2 by sirt3 promotes colorectal carcinogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203763/
https://www.ncbi.nlm.nih.gov/pubmed/30367038
http://dx.doi.org/10.1038/s41467-018-06812-y
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