title: Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis.
abstract: Aberrant expression of regulators for epigenetics is involved in tumorigenesis. There is an urgent need to identify and characterize regulators concerned with epigenetics in the early stages of hepatocarcinogenesis. In the present study, we found that the expression of coactivator-associated arginine methyltransferase 1 (CARM1), a histone methyltransferase that functions as a cofactor for nuclear hormone receptors and several transcription factors, was elevated in adenomas and aberrant in carcinomas during hepatocellular carcinogenesis. In addition to RNA expression, immunohistochemical staining of liver sections revealed that CARM1 was highly expressed in the nucleus of tumor marker glutathione S-transferase placental form (GST-P)-positive foci. Neoplastic transformation of GST-P-positive foci guides the formation of hepatocellular carcinomas. CARM1 expression was not elevated in GST-P-negative regions. Furthermore, a luciferase reporter analysis revealed that CARM1 activated the Gst-p promoter in H4IIE, a hepatocellular carcinoma cell line. This activation was mediated by the enhancer element responsible for the carcinogenic-specific expression of Gst-p and nuclear factor E2-related factor 2. Knockdown of Carm1 by shRNA in H4IIE cells inhibited cell proliferation. These findings suggest that aberrantly expressed CARM1 in tumor marker-positive cells promotes tumorigenesis in the early stages of hepatocarcinogenesis.
authors.affiliation: Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467‑8603, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Osada
authors.forename: Shugo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yoshimi
authors.forename: Miho
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Imagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D005982:Glutathione Transferase