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

Autor: Liang Shi, Hui Yan, Shuxian An, Mengqin Shen, Wenzhi Jia, Ruixue Zhang, Li Zhao, Gang Huang, Jianjun Liu
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Molecular Oncology, Vol 13, Iss 2, Pp 358-375 (2019)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12408
Popis: 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.
Databáze: Directory of Open Access Journals
Externí odkaz: