title: STAT3 acetylation-induced promoter methylation is associated with downregulation of the ARHI tumor-suppressor gene in ovarian cancer.
abstract: ARHI is a Ras-related imprinted tumor-suppressor gene that inhibits cancer cell growth and motility. ARHI is downregulated in the majority of ovarian cancer cells, and promoter methylation is considered to be associated with its loss of expression. however, the underlying mechanisms are not well understood. Thus, the present study aimed to investigate the specific functions of ARHI and its methylation in ovarian cancer cell proliferation. Furthermore, we examined the possible role of acetylated STAT3 in modulating the expression of ARHI and its methylation. In accordance with the majority of previous studies, reduced ARHI expression was found in epithelial ovarian cancer tissues and cancer cell lines as indicated by immunohistochemistry and RT-PCR. In addition, CpG islands I and II within ARHI promoter regions were partially methylated or hypermethylated in cancer cell lines (SKOV-3 and HO-8910) as analyzed by pyrosequencing assays, resulting in enhanced proliferation of the cancer cells. This proliferation was reversed by the administration of 5-aza-2'-deoxycytidine. Subsequently, we demonstrated that STAT3 acetylation was increased in HO-8910 cells, and the methylation status of CpG I was altered in response to the acetylation of STAT3 using western blotting. Finally, chromatin immunoprecipitation (ChIP) and IP analysis indicated that acetylated STAT3 bound to the ARHI promoter and recruited DNA methyltransferase 1 for genetic modification. In conclusion, acetylated STAT3-induced promoter gene methylation accounts for the loss of ARHI expression and cancer cell proliferation.
authors.affiliation: Department of Gynecology and Obstetrics, General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Geng
authors.initials: G
authors.lastname: Cui
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Wang
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Li
authors.forename: Yuan-Guang
authors.initials: YG
authors.lastname: Meng
authors.forename: Zheng
authors.initials: Z
authors.lastname: Guan
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Fan
authors.forename: Li-An
authors.initials: LA
authors.lastname: Li
authors.forename: Yi-Zhuo
authors.initials: YZ
authors.lastname: Yang
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: You
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Fu
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Yan
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
mesh_terms: D000107:Acetylation; D000328:Adult; D001374:Azacitidine / Q000031:analogs & derivatives / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C117386:DIRAS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D020741:rho GTP-Binding Proteins; D001374:Azacitidine