Journal Article

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

Zhang, Peng, Hoon, Dave S. B, Lee, Heehyoung, Herrmann, Andreas, Xin, Hong, Forman, Stephen J, Riggs, Arthur D, Yu, Hua, Yang, Chunmei, Wang, Zhenghe, Jove, Richard

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Acetylation / Analysis of Variance / Animals / antagonists & inhibitors / Antiestrogens / Biological Sciences / Blotting, Western / Breast cancer / breast neoplasms / Cancer / Cell culture / Cell growth / Cell Line, Tumor / Cell lines / Chromatin Immunoprecipitation / CpG islands / Demethylation / DNA / DNA Methylation / DNA Methylation - drug effects / DNA Methylation - genetics / DNA methyltransferase / drug effects / Estrogen receptors / Estrogens / Gene silencing / Genes / Genes, Tumor Suppressor / genetics / genomic islands / Humans / Immunoprecipitation / Lysine / Melanoma / metabolism / Methylation / Mice / Microscopy, Confocal / Microscopy, Fluorescence / pharmacology / Promoter Regions, Genetic / Promoter Regions, Genetic - genetics / Promoters / Real-Time Polymerase Chain Reaction / Resveratrol / Reverse Transcriptase Polymerase Chain Reaction / Skin cancer / Stat3 protein / STAT3 Transcription Factor / STAT3 Transcription Factor - antagonists & inhibitors / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Stilbenes / Stilbenes - pharmacology / T cell receptors / therapeutics / Transcription factors / Tumor cell line / Tumor cells / Tumor suppressor genes / Tumors