title: Involvement of EZH2, SUV39H1, G9a and associated molecules in pathogenesis of urethane induced mouse lung tumors: potential targets for cancer control.
abstract: In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control.
authors.affiliation: Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow -226001, India.
authors.forename: Manuraj
authors.initials: M
authors.lastname: Pandey
authors.affiliation: Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow -226001, India.
authors.forename: Satya
authors.initials: S
authors.lastname: Sahay
authors.affiliation: Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow -226001, India.
authors.forename: Prakash
authors.initials: P
authors.lastname: Tiwari
authors.affiliation: Laboratory Animals Services, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, India.
authors.forename: Daya S
authors.initials: DS
authors.lastname: Upadhyay
authors.affiliation: Dept. Medical Elementology and Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi, India.
authors.forename: Sarwat
authors.initials: S
authors.lastname: Sultana
authors.affiliation: Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow -226001, India. Electronic address: krishnag522@yahoo.co.in.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Gupta
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000032:analysis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D014520:Urethane / Q000633:toxicity*
chemical_list: D006657:Histones; C583174:MIRN138 microRNA, mouse; D035683:MicroRNAs; D012097:Repressor Proteins; D014520:Urethane; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2
keywords: EZH2; G9a histone methylation; Inositol hexaphosphate; Lung cancer; SUV39H1; Urethane