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Lactam-based HDAC inhibitors for anticancer chemotherapy: Restoration of RUNX3 by posttranslational modification and epigenetic control

Authors
 Misun Cho  ;  Eunhyun Choi  ;  Jae Hyun Kim  ;  Hwan Kim  ;  Hwan Mook Kim  ;  Jang Ik Lee  ;  Ki-Chul Hwang  ;  Hyun-Jung Kim  ;  Gyoonhee Han 
Citation
 CHEMMEDCHEM, Vol.9(3) : 649-656, 2014 
Journal Title
CHEMMEDCHEM
ISSN
 1860-7179 
Issue Date
2014
MeSH
Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology* ; 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 ; Core Binding Factor Alpha 3 Subunit/metabolism* ; Dose-Response Relationship, Drug ; Epigenesis, Genetic/drug effects* ; Gene Expression Profiling ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology* ; Histone Deacetylases/metabolism* ; Lactams/chemical synthesis ; Lactams/chemistry ; Lactams/pharmacology* ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Conformation ; Neoplasms, Experimental/drug therapy* ; 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
Keywords
drug discovery ; histone deacetylase ; inhibitors ; lactam ; runt-related transcription factor 3
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.
Full Text
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300393/abstract
DOI
10.1002/cmdc.201300393
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Hwang, Ki Chul(황기철)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98593
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