title: A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin.
abstract: Accumulation of genetic and epigenetic changes contributes to cancer development and progression. Compared with gene mutations or deletions, epigenetic changes are reversible, which alter the chromatin structure remodeling instead of changes in DNA sequence, and therefore become a promising strategy for chemotherapy. Histone deacetylases (HDACs) are a class of enzymes that responsible for the epigenetic regulation of gene expression. MPT0G030 is a potent and selective class I HDAC inhibitor which showed broad-spectrum cytotoxicity against various human cancer cell lines. in vitro fluorometric HDAC activity assay showed that MPT0G030 effectively inhibited Class I HDACs (HDAC1~3), which were overexpressed in many malignant neoplasms. Interestingly, MPT0G030 not only induced histone acetylation and tumor suppressor p21 transcription, but also redistributed E-cadherin and activated Protein Kinase C δ (PKCδ), which was linked to cell apoptosis and differentiation. Further, activation of PKCδ was demonstrated to be modulated through HDAC1. The in vivo anticancer activity of MPT0G030 and the importance of PKCδ were confirmed in the HT-29 tumor xenograft models. Taken together, those results indicate that MPT0G030, a class I HDAC inhibitor, has great potential as a new drug candidate for cancer therapy.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Wang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Li
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Liu
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019073:HT29 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D051745:Protein Kinase C-delta / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D051745:Protein Kinase C-delta; D056284:Histone Deacetylase 1