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Identification of a diketopiperazine-based O-GlcNAc transferase inhibitor sensitizing hepatocellular carcinoma to CDK9 inhibition.

التفاصيل البيبلوغرافية
العنوان: Identification of a diketopiperazine-based O-GlcNAc transferase inhibitor sensitizing hepatocellular carcinoma to CDK9 inhibition.
المؤلفون: Shan X; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Jiang R; Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, China., Gou D; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Xiang J; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Zhou P; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Xia J; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Wang K; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Huang A; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Tang N; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China., Huang L; Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, China.
المصدر: The FEBS journal [FEBS J] 2023 Sep; Vol. 290 (18), pp. 4543-4561. Date of Electronic Publication: 2023 Jun 05.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, UK : Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies, c2005-
مواضيع طبية MeSH: Carcinoma, Hepatocellular*/drug therapy , Carcinoma, Hepatocellular*/genetics , Liver Neoplasms*/drug therapy , Liver Neoplasms*/genetics, Humans ; N-Acetylglucosaminyltransferases/genetics ; N-Acetylglucosaminyltransferases/metabolism ; Glycosylation ; Protein Processing, Post-Translational ; Cyclin-Dependent Kinase 9/genetics ; Cyclin-Dependent Kinase 9/metabolism
مستخلص: O-GlcNAcylation (O-linked β-N-acetylglucosaminylation) is an important post-translational and metabolic process in cells that is implicated in a wide range of physiological processes. O-GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyses the transfer of O-GlcNAc to nucleocytoplasmic proteins. Aberrant glycosylation by OGT has been linked to a variety of diseases including cancer, neurodegenerative disorders and diabetes. Previously, we and others demonstrated that O-GlcNAcylation is notably elevated in hepatocellular carcinoma (HCC). The overexpression of O-GlcNAcylation promotes cancer progression and metastasis. Here, we report the identification of HLY838, a novel diketopiperazine-based OGT inhibitor with the ability to induce a global decrease in cellular O-GlcNAc. HLY838 enhances the in vitro and in vivo anti-HCC activity of CDK9 inhibitor by downregulating c-Myc and downstream E2F1 expression. Mechanistically, c-Myc is regulated by the CDK9 at the transcript level, and stabilized by OGT at the protein level. This work therefore demonstrates that HLY838 potentiates the antitumor responses of CDK9 inhibitor, providing an experimental rationale for developing OGT inhibitor as a sensitizing agent in cancer therapeutics.
(© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
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فهرسة مساهمة: Keywords: CDK9; O-GlcNAc transferase; c-Myc; hepatocellular carcinoma; inhibitor
المشرفين على المادة: EC 2.4.1.- (O-GlcNAc transferase)
EC 2.4.1.- (N-Acetylglucosaminyltransferases)
EC 2.7.11.22 (CDK9 protein, human)
EC 2.7.11.22 (Cyclin-Dependent Kinase 9)
تواريخ الأحداث: Date Created: 20230529 Date Completed: 20230921 Latest Revision: 20230921
رمز التحديث: 20240514
DOI: 10.1111/febs.16877
PMID: 37247228
قاعدة البيانات: MEDLINE
الوصف
تدمد:1742-4658
DOI:10.1111/febs.16877