title: Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity.
abstract: Altered epigenetic control of gene expression plays a substantial role in tumor development and progression. Accumulating studies suggest that somatic mutations of CREB binding proteins (CBP)/p300 occur in some cancer cells. CBP/p300 possess histone acetyltransferase (HAT) activity, and are involved in many cellular processes. In this study, we investigated the expression and functional role of CBP/p300 in hepatocellular carcinoma (HCC) using the specific inhibitor C646 of CBP/p300 HAT activity. We examined its effect on several apoptosis-related proteins and invasion-related genes. The results showed that CBP/p300 were highly expressed in HCC tissues and that expression of p300, but not of CBP, was strongly correlated with the malignant character of HCC. C646 inhibited proliferation of HCC cell lines in a dose dependent manner. C646 significantly augmented TRAIL-induced apoptotic sensitivity, which was accompanied by reduced levels of survivin, in HepG2, HLE and SK-HEP1 cells. C646 significantly inhibited invasion of Huh7, HLE and SK-HEP1 cells. The level of matrix metallopeptidase 15 (MMP15) mRNA expression was significantly reduced, whereas the level of laminin alpha 3 (LAMA3) and secreted phosphoprotein 1 (SPP1) mRNA expression was significantly increased in Huh7 cells following exposure to C646. In conclusion, our results suggest that CBP/p300 HAT activity has an important role in malignant transformation, proliferation, apoptotic sensitivity and invasion in HCC. CBP/p300 could be a promising therapeutic target in HCC.
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shiraki
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Takazumi
authors.initials: T
authors.lastname: Yada
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tameda
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.affiliation: Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D056945:Hep G2 Cells; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D007797:Laminin / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D053517:Matrix Metalloproteinase 15 / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009578:Nitrobenzenes; D053495:Osteopontin / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D047069:Pyrazolones; D012333:RNA, Messenger / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics*
chemical_list: C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D007797:Laminin; D009578:Nitrobenzenes; D011720:Pyrazoles; D047069:Pyrazolones; D012333:RNA, Messenger; C506895:SPP1 protein, human; D053495:Osteopontin; C095567:laminin alpha 3; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors; D053517:Matrix Metalloproteinase 15