title: Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation.
abstract: The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1-STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000107:Acetylation; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D000077185:Resveratrol