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SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer

Lactate dehydrogenase B (LDHB) is a glycolytic enzyme that catalyses the conversion of lactate and NAD (+) to pyruvate, NADH and H(+). Protons (H(+)) generated by LDHB promote lysosomal acidification and autophagy in cancer, but how this role is regulated has not been defined. In this study, we iden...

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Autores principales: Shi, Liang, Yan, Hui, An, Shuxian, Shen, Mengqin, Jia, Wenzhi, Zhang, Ruixue, Zhao, Li, Huang, Gang, Liu, Jianjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360364/
https://www.ncbi.nlm.nih.gov/pubmed/30443978
http://dx.doi.org/10.1002/1878-0261.12408
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author Shi, Liang
Yan, Hui
An, Shuxian
Shen, Mengqin
Jia, Wenzhi
Zhang, Ruixue
Zhao, Li
Huang, Gang
Liu, Jianjun
author_facet Shi, Liang
Yan, Hui
An, Shuxian
Shen, Mengqin
Jia, Wenzhi
Zhang, Ruixue
Zhao, Li
Huang, Gang
Liu, Jianjun
author_sort Shi, Liang
collection PubMed
description Lactate dehydrogenase B (LDHB) is a glycolytic enzyme that catalyses the conversion of lactate and NAD (+) to pyruvate, NADH and H(+). Protons (H(+)) generated by LDHB promote lysosomal acidification and autophagy in cancer, but how this role is regulated has not been defined. In this study, we identified an important post‐translational mechanism by which LDHB is regulated during autophagy in cancer cells. Mass spectrometry revealed that protein sirtuin 5 (SIRT5) is a binding partner of LDHB that deacetylated LDHB at lysine‐329, thereby promoting its enzymatic activity. Deacetylated LDHB increased autophagy and accelerated the growth of colorectal cancer (CRC) cells. Notably, SIRT5 knockout or inhibition by GW5074 increased LDHB acetylation at K329 and inhibited LDHB activity, which downregulated autophagy and CRC cell growth in vitro and in vivo. Clinically, the LDHB‐Ac‐K329 staining score in CRC tissues was lower than that in corresponding peritumour tissues. Low LDHB‐Ac‐K329 status was associated with malignant progression of human CRC and served as a potential prognostic indicator for patients with CRC. Altogether, we conclude that SIRT5‐induced deacetylation of LDHB triggers hyperactivation of autophagy, a key event in tumorigenesis. Thus, the SIRT5/LDHB pathway may represent a novel target for treating CRC.
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spelling pubmed-63603642019-02-14 SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer Shi, Liang Yan, Hui An, Shuxian Shen, Mengqin Jia, Wenzhi Zhang, Ruixue Zhao, Li Huang, Gang Liu, Jianjun Mol Oncol Research Articles Lactate dehydrogenase B (LDHB) is a glycolytic enzyme that catalyses the conversion of lactate and NAD (+) to pyruvate, NADH and H(+). Protons (H(+)) generated by LDHB promote lysosomal acidification and autophagy in cancer, but how this role is regulated has not been defined. In this study, we identified an important post‐translational mechanism by which LDHB is regulated during autophagy in cancer cells. Mass spectrometry revealed that protein sirtuin 5 (SIRT5) is a binding partner of LDHB that deacetylated LDHB at lysine‐329, thereby promoting its enzymatic activity. Deacetylated LDHB increased autophagy and accelerated the growth of colorectal cancer (CRC) cells. Notably, SIRT5 knockout or inhibition by GW5074 increased LDHB acetylation at K329 and inhibited LDHB activity, which downregulated autophagy and CRC cell growth in vitro and in vivo. Clinically, the LDHB‐Ac‐K329 staining score in CRC tissues was lower than that in corresponding peritumour tissues. Low LDHB‐Ac‐K329 status was associated with malignant progression of human CRC and served as a potential prognostic indicator for patients with CRC. Altogether, we conclude that SIRT5‐induced deacetylation of LDHB triggers hyperactivation of autophagy, a key event in tumorigenesis. Thus, the SIRT5/LDHB pathway may represent a novel target for treating CRC. John Wiley and Sons Inc. 2018-12-03 2019-02 /pmc/articles/PMC6360364/ /pubmed/30443978 http://dx.doi.org/10.1002/1878-0261.12408 Text en © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Shi, Liang
Yan, Hui
An, Shuxian
Shen, Mengqin
Jia, Wenzhi
Zhang, Ruixue
Zhao, Li
Huang, Gang
Liu, Jianjun
SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
title SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
title_full SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
title_fullStr SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
title_full_unstemmed SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
title_short SIRT5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
title_sort sirt5‐mediated deacetylation of ldhb promotes autophagy and tumorigenesis in colorectal cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360364/
https://www.ncbi.nlm.nih.gov/pubmed/30443978
http://dx.doi.org/10.1002/1878-0261.12408
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