Silencing of OGDHL promotes liver cancer metastasis by enhancing hypoxia inducible factor 1 α protein stability

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases associated with a high rate of mortality. Frequent intrahepatic spread, extrahepatic metastasis, and tumor invasiveness are the main factors responsible for the poor prognosis of patients with HCC. Hypoxia‐inducible factor 1...

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Published in:	Cancer science Vol. 114; no. 4; pp. 1309 - 1323
Main Authors:	Dai, Weiqi, Li, Yueyue, Sun, Weijie, Ji, Meng, Bao, Renjun, Chen, Jianqing, Xu, Shuqi, Dai, Ying, Chen, Yiming, Liu, Wenjing, Ge, Chao, Sun, Wei, Mo, Wenhui, Guo, Chuanyong, Xu, Xuanfu
Format:	Journal Article
Language:	English
Published:	England John Wiley & Sons, Inc 01-04-2023 John Wiley and Sons Inc
Subjects:	Antibodies Cancer therapies Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell migration Cell Movement - genetics Dehydrogenases Gene Expression Regulation, Neoplastic Hepatocellular carcinoma HIF‐1α Humans Hypoxia Hypoxia-inducible factor 1 Hypoxia-Inducible Factor 1 - metabolism Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-inducible factor 1a Invasiveness Liver cancer Liver Neoplasms - pathology Metabolites Metastases Metastasis OGDHL Original Plasmids Prognosis Protein Stability Proteins tricarboxylic acid cycle Tumors China tricarboxylic acid cycle HIF-1α OGDHL liver cancer metastasis
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Summary:	Hepatocellular carcinoma (HCC) is one of the most common malignant diseases associated with a high rate of mortality. Frequent intrahepatic spread, extrahepatic metastasis, and tumor invasiveness are the main factors responsible for the poor prognosis of patients with HCC. Hypoxia‐inducible factor 1 (HIF‐1) has been verified to play a critical role in the metastasis of HCC. HIFs are also known to be modulated by small molecular metabolites, thus highlighting the need to understand the complexity of their cellular regulation in tumor metastasis. In this study, lower expression levels of oxoglutarate dehydrogenase‐like (OGDHL) were strongly correlated with aggressive clinicopathologic characteristics, such as metastasis and invasion in three independent cohorts featuring a total of 281 postoperative HCC patients. The aberrant expression of OGDHL reduced cell invasiveness and migration in vitro and HCC metastasis in vivo, whereas the silencing of OGDHL promoted these processes in HCC cells. The pro‐metastatic role of OGDHL downregulation is most likely attributed to its upregulation of HIF‐1α transactivation activity and the protein stabilization by promoting the accumulation of L‐2‐HG to prevent the activity of HIF‐1α prolyl hydroxylases, which subsequently causes an epithelial–mesenchymal transition process in HCC cells. These results demonstrate that OGDHL is a dominant factor that modulates the metastasis of HCC. In patients with HCC, lower expression of the enzyme OGDHL is significantly associated with metastasis and invasion in three independent cohorts featuring a total of 281 postoperative HCC patients. The pro‐metastatic activity of OGDHL downregulation is most likely attributed to its upregulation of HIF‐1α transactivation activity and the stabilization of HIF‐1α protein by promoting the formation of L‐2‐HG. OGDHL is a critical factor that modulates the epithelial‐mesenchymal transition response in HCC.
Bibliography:	Weiqi Dai, Yueyue Li, Weijie Sun and Meng Ji contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1347-9032 1349-7006
DOI:	10.1111/cas.15540