Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis
Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis
复制标题
DNMT1 下调 FOXO3a 促进乳腺癌干细胞特性和肿瘤发生
DOI：
10.1038/s41418-019-0389-3
复制
发表时间：
2020-03-01
影响因子：
12.4
通讯作者：
He, Zhimin
中科院分区：
文献类型：
--
作者：
Liu, Hao;Song, Ying;He, Zhimin
乳腺癌干细胞（BCSCs）是肿瘤起始细胞，能够自我更新，具有高度致瘤性和化疗抗性。因此，鉴定对乳腺癌干细胞功能至关重要的因子对于治疗方法的开发至关重要。在此，我们报道DNMT1介导的FOXO3a启动子高甲基化导致乳腺癌中FOXO3a表达下调。FOXO3a在功能上与抑制FOXM1/SOX2信号通路相关，并因此抑制乳腺癌干细胞特性和致瘤性。此外，我们发现SOX2直接反式激活DNMT1表达，从而改变甲基化图谱，这反过来又反馈抑制FOXO3a表达。抑制DNMT活性通过调节乳腺癌中的FOXO3a/FOXM1/SOX2信号通路抑制肿瘤生长。在临床上，我们观察到FOXO3a与FOXM1/SOX2/DNMT1表达水平之间存在显著的负相关，并且FOXO3a表达缺失或FOXM1、SOX2和DNMT1表达增加预示着乳腺癌预后不良。总之，我们的研究结果表明DNMT1/FOXO3a/FOXM1/SOX2通路在调节乳腺癌干细胞特性方面具有重要作用，为乳腺癌提示了潜在的治疗靶点。
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.