A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin
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Li-Ting Wang1, Jing-Ping Liou2, Yu-Hsuan Li2, Yi-Min Liu2, Shiow-Lin Pan3,* and Che-Ming Teng1,*
1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
3 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
* These authors contributed equally to this work
Shiow-Lin Pan, email:
Che-Ming Teng, email:
Keywords: MPT0G030, PKCδ, E-cadherin, HDAC, differentiation
Received: May 16, 2014 Accepted: June 30, 2014 Published: July 1, 2014
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.
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