表观遗传学
乳腺癌
福克斯A1
染色质
转录因子
下调和上调
基因
发起人
加压器
医学
癌症研究
抑制因子
生物
基因表达
遗传学
癌症
内科学
作者
Jiahui Zhang,Nanyan Miao,Liyan Lao,Wen Dong,Jiawen Wang,Xiaofeng Zhu,Yongsheng Huang,Hongxin Lin,Wenfeng Zeng,W. Zhang,Li Kuo Tan,Xiaoqing Yuan,Xiaofeng Zeng,Jingkun Zhu,Xueman Chen,Erwei Song,Lixuan Yang,Yan Nie,Di Huang
标识
DOI:10.1002/advs.202307660
摘要
Basal-like breast cancer (BLBC) is the most aggressive molecular subtype of breast cancer with worse prognosis and fewer treatment options. The underlying mechanisms upon BLBC transcriptional dysregulation and its upstream transcription factors (TFs) remain unclear. Here, among the hyperactive candidate TFs of BLBC identified by bioinformatic analysis, POU4F1 is uniquely upregulated in BLBC and is associated with poor prognosis. POU4F1 is necessary for the tumor growth and malignant phenotypes of BLBC through regulating G1/S transition by direct binding at the promoter of CDK2 and CCND1. More importantly, POU4F1 maintains BLBC identity by repressing ERα expression through CDK2-mediated EZH2 phosphorylation and subsequent H3K27me3 modification in ESR1 promoter. Knocking out POU4F1 in BLBC cells reactivates functional ERα expression, rendering BLBC sensitive to tamoxifen treatment. In-depth epigenetic analysis reveals that the subtype-specific re-configuration and activation of the bivalent chromatin in the POU4F1 promoter contributes to its unique expression in BLBC, which is maintained by DNA demethylase TET1. Together, these results reveal a subtype-specific epigenetically activated TF with critical role in promoting and maintaining BLBC, suggesting that POU4F1 is a potential therapeutic target for BLBC.
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