Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis

作者：Hao Liu, Ying Song, Huishi Qiu, Yanzhen Liu, Kai Luo, Yanmei Yi, Guanmin Jiang, Minying Lu, Zhijie Zhang, Jiang Yin, Shanshan Zeng, Xiangzhou Chen, Min Deng, Xiaoting Jia, Yixue Gu, Danyang Chen, Guopei Zheng, Zhimin He · 发表于：Cell Death and Differentiation · 年份：2019 · DOI：10.1038/s41418-019-0389-3 · 被引用次数：263 · 研究领域：FOXO transcription factor regulation、Cancer-related molecular mechanisms research、Cancer Cells and Metastasis

Breast cancer stem cells (BCSCs) are tumor initiating cells that can self-renew and are highly tumorigenic and chemoresistant. Therefore, the identification of factors critical for BCSC function is vital for the development of therapies. Here, we report that DNMT1-mediated FOXO3a promoter hypermethylation leads to downregulation of FOXO3a expression in breast cancer. FOXO3a is functionally related to the inhibition of FOXM1/SOX2 signaling and to the consequent suppression of BCSCs properties and tumorigenicity. Moreover, we found that SOX2 directly transactivates DNMT1 expression and thereby alters the methylation landscape, which in turn feedback inhibits FOXO3a expression. Inhibition of DNMT activity suppressed tumor growth via regulation of FOXO3a/FOXM1/SOX2 signaling in breast cancer. Clinically, we observed a significant inverse correlation between FOXO3a and FOXM1/SOX2/DNMT1 expression levels, and loss of FOXO3a expression or increased expression of FOXM1, SOX2, and DNMT1 predicted poor prognosis in breast cancer. Collectively, our findings suggest an important role of the DNMT1/FOXO3a/FOXM1/SOX2 pathway in regulating BCSCs properties, suggesting potential therapeutic targets for breast cancer.