دورية أكاديمية
C-terminal binding protein 2 is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma.
| العنوان: | C-terminal binding protein 2 is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma. |
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| المؤلفون: | Cheung CHY; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Cheng CK; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Leung KT; Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China., Zhang C; Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China., Ho CY; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Luo X; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Kam AYF; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Xia T; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Wan TSK; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Pitts HA; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Chan NPH; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Cheung JS; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Wong RSM; Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China., Zhang XB; Department of Medicine, Loma Linda University, Loma Linda, California., Ng MHL; Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China. |
| المصدر: | Blood advances [Blood Adv] 2024 May 14; Vol. 8 (9), pp. 2217-2234. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Society of Hematology, [2016]- |
| مواضيع طبية MeSH: | Alcohol Oxidoreductases*/metabolism , Alcohol Oxidoreductases*/antagonists & inhibitors , Interferon Regulatory Factors*/metabolism , Interferon Regulatory Factors*/genetics , Multiple Myeloma*/metabolism , Multiple Myeloma*/drug therapy , Multiple Myeloma*/pathology , Proto-Oncogene Proteins c-myc*/metabolism , Co-Repressor Proteins*/antagonists & inhibitors , Co-Repressor Proteins*/metabolism, Animals ; Humans ; Mice ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Signal Transduction/drug effects ; Tumor Suppressor Proteins/metabolism |
| مستخلص: | Abstract: Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent antitumor effects against MM in vitro and in vivo, with marked repression of the MYC-IRF4 network genes. Mechanistically, CTBP2 impeded the transcription of MYC and IRF4 by histone H3 lysine 27 deacetylation (H3K27ac) and indirectly via activation of the MYC repressor IFIT3. In addition, activation of the interferon gene signature by CTBP2 suggested its concomitant immunomodulatory role in MM. Epigenetic studies have revealed the contribution of polycomb-mediated silencing and DNA methylation to CTBP2 inactivation in MM. Notably, inhibitors of Enhance of zeste homolog 2, histone deacetylase, and DNA methyltransferase, currently under evaluation in clinical trials, were effective in restoring CTBP2 expression in MM. Our findings indicated that the loss of CTBP2 plays an essential role in myelomagenesis and deciphers an additional mechanistic link to MYC-IRF4 dysregulation in MM. We envision that the identification of novel critical regulators will facilitate the development of selective and effective approaches for treating this MYC/IRF4-addicted malignancy. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.) |
| المشرفين على المادة: | EC 1.1.- (Alcohol Oxidoreductases) 0 (Interferon Regulatory Factors) 0 (Proto-Oncogene Proteins c-myc) 0 (Tumor Suppressor Proteins) EC 1.1.- (CTBP2 protein, human) 0 (Co-Repressor Proteins) |
| تواريخ الأحداث: | Date Created: 20240308 Date Completed: 20240514 Latest Revision: 20240603 |
| رمز التحديث: | 20240603 |
| مُعرف محوري في PubMed: | PMC11061227 |
| DOI: | 10.1182/bloodadvances.2023010218 |
| PMID: | 38457926 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder | تدمد: | 2473-9537 |
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| DOI: | 10.1182/bloodadvances.2023010218 |