1. Lactam-based HDAC inhibitors for anticancer chemotherapy: restoration of RUNX3 by posttranslational modification and epigenetic control.
- Author
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Cho M, Choi E, Kim JH, Kim H, Kim HM, Lee JI, Hwang KC, Kim HJ, and Han G
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Core Binding Factor Alpha 3 Subunit antagonists & inhibitors, Core Binding Factor Alpha 3 Subunit chemistry, Core Binding Factor Alpha 3 Subunit genetics, Dose-Response Relationship, Drug, Gene Expression Profiling, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Lactams chemical synthesis, Lactams chemistry, Mice, Mice, Nude, Models, Molecular, Molecular Conformation, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Protein Stability drug effects, RNA, Messenger antagonists & inhibitors, RNA, Messenger genetics, RNA, Messenger metabolism, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Core Binding Factor Alpha 3 Subunit metabolism, Epigenesis, Genetic drug effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Lactams pharmacology, Neoplasms, Experimental drug therapy
- Abstract
Expression and stability of the tumor suppressor runt-related transcription factor 3 (RUNX3) are regulated by histone deacetylase (HDAC). HDAC inhibition alters epigenetic and posttranslational stability of RUNX3, leading to tumor suppression. However, HDAC inhibitors can nonselectively alter global gene expression through chromatin remodeling. Thus, lactam-based HDAC inhibitors were screened to identify potent protein stabilizers that maintain RUNX3 stability by acetylation. RUNX activity and HDAC inhibition were determined for 111 lactam-based analogues through a cell-based RUNX activation and HDAC inhibition assay. 3-[1-(4-Bromobenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxypropanamide (11-8) significantly increased RUNX3 acetylation and stability with relatively low RUNX3 mRNA expression and HDAC inhibitory activity. This compound showed significant antitumor effects, which were stronger than SAHA, in an MKN28 xenograft model. Thus, we propose a novel strategy, in which HDAC inhibitors serve as antitumor chemotherapeutic agents that selectively target epigenetic regulation and protein stability of RUNX3., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...
- Published
- 2014
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