Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Proc Natl Acad Sci U S A. 2012 May 15;109(20):7765-9. doi: 10.1073/pnas.1205132109. Epub 2012 Apr 30.
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.
肿瘤抑制基因启动子高甲基化的机制尚不清楚。在这里，我们报告致癌转录因子 STAT3 的赖氨酸乙酰化在肿瘤中升高。我们还表明，通过遗传改变 STAT3 上的赖氨酸 685 可减少肿瘤生长，这伴随着几个肿瘤抑制基因的去甲基化和重新激活。此外，在培养的肿瘤细胞和肿瘤中突变 STAT3 上的赖氨酸 685 会破坏 DNA 甲基转移酶 1-STAT3 相互作用。这些观察结果通过使用乙酰化抑制剂白藜芦醇得到证实。此外，三阴性乳腺癌细胞中乙酰化 STAT3 的减少导致雌激素受体-α基因的去甲基化和激活，使肿瘤细胞对雌激素拮抗剂敏感。我们的结果还表明 STAT3 乙酰化与黑色素瘤中雌激素受体-α的甲基化之间存在相关性，这可预测黑色素瘤的进展。综上所述，这些结果表明 STAT3 乙酰化在调节 CpG 岛甲基化中的作用，这可能部分解释了癌症中异常基因沉默的原因。这些发现还为针对乙酰化 STAT3 进行化学预防和癌症治疗提供了依据。
