Lactam‐Based HDAC Inhibitors for Anticancer Chemotherapy: Restoration of RUNX3 by Posttranslational Modification and Epigenetic Control
Copyright policy )Lactam‐Based HDAC Inhibitors for Anticancer Chemotherapy: Restoration of RUNX3 by Posttranslational Modification and Epigenetic Control
AbstractExpression 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.
- University Health System United States
- Yonsei University Korea (Republic of)
- Yonsei University Health System Korea (Republic of)
- Gachon University Korea (Republic of)
- Yonsei University Medical Library Korea (Republic of)
Experimental/drug therapy*, Models, Molecular, Nude, Molecular Conformation, Messenger/metabolism, Epigenesis, Genetic, Cell Proliferation/drug effects, Mice, Models, Neoplasms, Antineoplastic Agents/chemistry, inhibitors, Experimental/pathology, Lactams/pharmacology*, Antineoplastic Agents/chemical synthesis, Protein Stability, Histone Deacetylase Inhibitors/chemistry, Core Binding Factor Alpha 3 Subunit/chemistry, lactam, Core Binding Factor Alpha 3 Subunit/genetics, Drug, Lactams/chemical synthesis, Core Binding Factor Alpha 3 Subunit/antagonists & inhibitors, Histone Deacetylase Inhibitors/chemical synthesis, Lactams, Histone Deacetylase Inhibitors/pharmacology*, 610, Mice, Nude, Antineoplastic Agents, Histone Deacetylases/metabolism*, Histone Deacetylases, drug discovery, Dose-Response Relationship, Antineoplastic Agents/pharmacology*, Structure-Activity Relationship, 615, Protein Stability/drug effects, Animals, RNA, Messenger, Experimental/metabolism, Cell Proliferation, Dose-Response Relationship, Drug, Core Binding Factor Alpha 3 Subunit/metabolism*, Gene Expression Profiling, Molecular, Neoplasms, Experimental, Lactams/chemistry, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, Core Binding Factor Alpha 3 Subunit, runt-related transcription factor 3, histone deacetylase, RNA, Messenger/genetics, Genetic/drug effects*, Epigenesis, Messenger/antagonists & inhibitors
Experimental/drug therapy*, Models, Molecular, Nude, Molecular Conformation, Messenger/metabolism, Epigenesis, Genetic, Cell Proliferation/drug effects, Mice, Models, Neoplasms, Antineoplastic Agents/chemistry, inhibitors, Experimental/pathology, Lactams/pharmacology*, Antineoplastic Agents/chemical synthesis, Protein Stability, Histone Deacetylase Inhibitors/chemistry, Core Binding Factor Alpha 3 Subunit/chemistry, lactam, Core Binding Factor Alpha 3 Subunit/genetics, Drug, Lactams/chemical synthesis, Core Binding Factor Alpha 3 Subunit/antagonists & inhibitors, Histone Deacetylase Inhibitors/chemical synthesis, Lactams, Histone Deacetylase Inhibitors/pharmacology*, 610, Mice, Nude, Antineoplastic Agents, Histone Deacetylases/metabolism*, Histone Deacetylases, drug discovery, Dose-Response Relationship, Antineoplastic Agents/pharmacology*, Structure-Activity Relationship, 615, Protein Stability/drug effects, Animals, RNA, Messenger, Experimental/metabolism, Cell Proliferation, Dose-Response Relationship, Drug, Core Binding Factor Alpha 3 Subunit/metabolism*, Gene Expression Profiling, Molecular, Neoplasms, Experimental, Lactams/chemistry, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, Core Binding Factor Alpha 3 Subunit, runt-related transcription factor 3, histone deacetylase, RNA, Messenger/genetics, Genetic/drug effects*, Epigenesis, Messenger/antagonists & inhibitors
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