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• W4366821906 abstract "Article24 April 2023 Source DataTransparent process Glutamate dehydrogenase1 supports HIF-1α stability to promote colorectal tumorigenesis under hypoxia Kunhua Hu Kunhua Hu orcid.org/0000-0001-9422-7828 Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Contribution: Conceptualization, Data curation, Formal analysis, Validation, ​Investigation, Methodology Search for more papers by this author Yufeng Ding Yufeng Ding orcid.org/0009-0003-5803-2777 School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China Contribution: Resources, Formal analysis, ​Investigation, Project administration, Writing - review & editing Search for more papers by this author Hongwen Zhu Hongwen Zhu orcid.org/0000-0002-2116-4245 Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Contribution: Data curation, Software, Formal analysis, Validation, ​Investigation, Visualization, Methodology Search for more papers by this author Xiaoqian Jing Xiaoqian Jing Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Contribution: Resources, Formal analysis, Validation, ​Investigation, Visualization Search for more papers by this author Weiling He Corresponding Author Weiling He [email protected] The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Contribution: Resources, Methodology Search for more papers by this author Hua Yu Corresponding Author Hua Yu [email protected] orcid.org/0000-0003-0411-1085 School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China Contribution: Resources, Formal analysis, Supervision, Validation, ​Investigation, Methodology, Project administration Search for more papers by this author Xiongjun Wang Corresponding Author Xiongjun Wang [email protected] [email protected] orcid.org/0000-0003-3946-5748 School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China Contribution: Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Kunhua Hu Kunhua Hu orcid.org/0000-0001-9422-7828 Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Contribution: Conceptualization, Data curation, Formal analysis, Validation, ​Investigation, Methodology Search for more papers by this author Yufeng Ding Yufeng Ding orcid.org/0009-0003-5803-2777 School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China Contribution: Resources, Formal analysis, ​Investigation, Project administration, Writing - review & editing Search for more papers by this author Hongwen Zhu Hongwen Zhu orcid.org/0000-0002-2116-4245 Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Contribution: Data curation, Software, Formal analysis, Validation, ​Investigation, Visualization, Methodology Search for more papers by this author Xiaoqian Jing Xiaoqian Jing Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Contribution: Resources, Formal analysis, Validation, ​Investigation, Visualization Search for more papers by this author Weiling He Corresponding Author Weiling He [email protected] The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Contribution: Resources, Methodology Search for more papers by this author Hua Yu Corresponding Author Hua Yu [email protected] orcid.org/0000-0003-0411-1085 School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China Contribution: Resources, Formal analysis, Supervision, Validation, ​Investigation, Methodology, Project administration Search for more papers by this author Xiongjun Wang Corresponding Author Xiongjun Wang [email protected] [email protected] orcid.org/0000-0003-3946-5748 School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China Contribution: Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Author Information Kunhua Hu1,†, Yufeng Ding2,†, Hongwen Zhu3,†, Xiaoqian Jing4,†, Weiling He *,5, Hua Yu *,2 and Xiongjun Wang *,*,2 1Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 2School of Life Sciences, Precise Genome Engineering Center, Guangzhou University, Guangzhou, China 3Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China 4Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 5The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China † These authors contributed equally to this work *Corresponding author. Tel: +86-020-87755766; E-mail: [email protected] *Corresponding author. Tel: +86-020-86236055; E-mail: [email protected] *Corresponding author. Tel: +86-020-86236055; E-mail: [email protected]; [email protected] The EMBO Journal (2023)e112675https://doi.org/10.15252/embj.2022112675 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Tumor cells surviving hypoxic stress acquire the ability to drive cancer progression. To explore the contribution of dehydrogenases to the low oxygen concentration response, we used siRNAs targeting 163 dehydrogenase-coding genes and discovered that glutamate dehydrogenase 1 (GDH1) plays a critical role in regulating colorectal cancer (CRC) cell survival under hypoxia. We observed that GDH1 deficiency had an inhibitory effect on CRC occurrence and impaired hypoxia-inducible factor 1-alpha (HIF-1α) stability even under hypoxia. Mechanistically, hypoxia triggered p300 recruitment to GDH1, promoting its acetylation at K503 and K527. GDH1 acetylation at K527 induced the formation of a GDH1 complex with EGLN1/HIF-1α; in contrast, GDH1 acetylation at K503 reinforced its affinity for α-ketoglutarate (αKG), and glutamate production. In line with this view, αKG is a product of GDH1 under normoxia, but hypoxia stimulation reversed GDH1 enzyme activity and αKG consumption by the EGLN1/HIF-1α complex, increasing HIF-1α stability and promoting CRC progression. Clinically, hypoxia-modulated GDH1 AcK503/527 can be used as a biomarker of CRC progression and is a potential target for CRC treatment. Synopsis This study identifies αKG metabolic enzyme glutamate dehydrogenase 1 (GDH1) as a major factor controling colorectal cancer (CRC) by facilitating HIF-1a-dependent cancer signaling. GDH1 is required for hypoxia response in CRC cells and associated with poor prognosis in patients. GDH1 depletion in the mouse intestine impairs CRC formation. Hypoxia-induced acetylation of GDH1 by p300 is required for HIF-1α stability. Hypoxia-induced GDH1 acetylation at K503 reverses its dehydrogenase activity. Hypoxia-induced GDH1 acetylation at K527 anchors GDH1 to the EGLN1/HIF-1α complex. GDH1 acetylation is required for solid tumor formation and correlates with poor CRC prognosis. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 0,Issue 0,This cover highlights the article Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy by Lorenzo Picchianti, Victor Sanchez de Medina Hernandez, Ni Zhan, Yasin Dagdas and colleagues. Shuffled ATG8 interacting motifs bridge UFMylation and autophagy at the endoplasmic reticulum. (Cover concept by the authors, scientific illustration by Marzia Munafò, www.munafomarzia.com) Latest OnlineView all ReferencesRelatedDetailsLoading ..." @default.
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• W4366821906 title "Glutamate dehydrogenase1 supports <scp>HIF</scp> ‐1α stability to promote colorectal tumorigenesis under hypoxia" @default.
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