1. Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis
- Author
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Zhimin He, Guopei Zheng, Guanmin Jiang, Jiang Yin, Minying Lu, Zhijie Zhang, Danyang Chen, Ying Song, Xiangzhou Chen, Hao Liu, Yanzhen Liu, Xiaoting Jia, Min Deng, Yixue Gu, Huishi Qiu, Yanmei Yi, Kai Luo, and Shanshan Zeng
- Subjects
0301 basic medicine ,DNA (Cytosine-5-)-Methyltransferase 1 ,Carcinogenesis ,Down-Regulation ,Mice, Nude ,Breast Neoplasms ,Biology ,medicine.disease_cause ,Article ,Tumour biomarkers ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,SOX2 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Cell Proliferation ,Feedback, Physiological ,Cancer stem cells ,SOXB1 Transcription Factors ,Forkhead Box Protein M1 ,Forkhead Box Protein O3 ,Cell Biology ,Methylation ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer research ,DNMT1 ,FOXM1 ,Neoplastic Stem Cells ,Female ,Stem cell ,Signal Transduction - Abstract
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.
- Published
- 2019