title: Lactam-based HDAC inhibitors for anticancer chemotherapy: restoration of RUNX3 by posttranslational modification and epigenetic control.
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.
authors.affiliation: Translational Research Center for Protein Function Control (TRCP), Department of Biotechnology and Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-752 (Republic of Korea).
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Eunhyun
authors.initials: E
authors.lastname: Choi
authors.forename: Jae Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Jang Ik
authors.initials: JI
authors.lastname: Lee
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D050677:Core Binding Factor Alpha 3 Subunit / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050677:Core Binding Factor Alpha 3 Subunit; D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D012333:RNA, Messenger; C493729:Runx3 protein, human; D006655:Histone Deacetylases
keywords: drug discovery; histone deacetylase; inhibitors; lactam; runt-related transcription factor 3