title: Tip60 is regulated by circadian transcription factor clock and is involved in cisplatin resistance.
abstract: Histone modification is important for maintaining chromatin structure and function. Recently, histone acetylation has been shown to have a critical regulatory role in both transcription and DNA repair. We report here that expression of histone acetyltransferase (HAT) genes is associated with cisplatin resistance. We found that Tip60 is overexpressed in cisplatin-resistant cells. The expression of two other HAT genes, HAT1 and MYST1, did not differ between drug-sensitive and -resistant cells. Knockdown of Tip60 expression rendered cells sensitive to cisplatin but not to oxaliplatin, vincristine, and etoposide. Tip60 expression is significantly correlated with cisplatin sensitivity in human lung cancer cell lines. Interestingly, the promoter region of the Tip60 gene contains several E boxes, and its expression was regulated by the E-box binding circadian transcription factor Clock but not by other E-box binding transcription factors such as c-Myc, Twist, and USF1. Hyperacetylation of H3K14 and H4K16 was found in cisplatin-resistant cells. The microarray study reveals that several genes for DNA repair are down-regulated by the knockdown of Tip60 expression. Our data show that HAT gene expression is required for cisplatin resistance and suggest that Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation.
authors.affiliation: Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Takako
authors.initials: T
authors.lastname: Noguchi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohmiya
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kidani
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tawara
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D056926:CLOCK Proteins; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D002945:Cisplatin