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

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 hypermethy...

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Bibliographic Details
Published in:Cell death and differentiation 2020-03, Vol.27 (3), p.966-983
Main Authors: Liu, Hao, Song, Ying, Qiu, Huishi, Liu, Yanzhen, Luo, Kai, Yi, Yanmei, Jiang, Guanmin, Lu, Minying, Zhang, Zhijie, Yin, Jiang, Zeng, Shanshan, Chen, Xiangzhou, Deng, Min, Jia, Xiaoting, Gu, Yixue, Chen, Danyang, Zheng, Guopei, He, Zhimin
Format: Article
Language:English
Subjects:
13/1
13/109
13/31
13/51
13/89
692/699/67/1857
692/699/67/71
Apoptosis
Biochemistry
Biomedical and Life Sciences
Breast cancer
Cell Biology
Cell Cycle Analysis
DNMT1 protein
FOXO3 protein
Life Sciences
Stem Cells
Therapeutic applications
Tumorigenesis
Tumorigenicity
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-019-0389-3