The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer
The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer
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FOXN3-NEAT1-SIN3A 阻遏物复合物促进激素反应性乳腺癌的进展
DOI：
10.1172/jci94233
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发表时间：
2017-09-01
影响因子：
15.9
通讯作者：
Shang, Yongfeng
中科院分区：
文献类型：
--
作者：
Li, Wanjin;Zhang, Zihan;Shang, Yongfeng
叉头转录因子FOXN 3的病理生理功能仍有待探讨。在这里，我们报告说，FOXN 3是一个转录抑制因子，是物理上与雌激素受体阳性（ER+）细胞中的SIN 3A阻遏复合物。RNA免疫沉淀偶联高通量测序确定NEAT 1，一种雌激素诱导的长非编码RNA，是FOXN 3与SIN 3A复合物相互作用所必需的。ChIP-Seq和RNA基因组靶点的深度测序显示，FOXN 3-NEAT 1-SIN 3A复合物抑制包括GATA 3在内的基因，这些基因与上皮细胞向间充质细胞转化（EMT）密切相关。我们证明了FOXN 3-NEAT 1-SIN 3A复合物在体外促进乳腺癌细胞的EMT和侵袭以及在体内促进乳腺癌的传播和转移。有趣的是，FOXN 3-NEAT 1-SIN 3A复合物反式抑制ER本身，在转录调控中形成负反馈环。乳腺癌进展过程中FOXN 3和NEAT 1表达的升高对应于GATA 3表达的降低，高水平的FOXN 3和NEAT 1与较高的组织学分级和不良预后密切相关。我们的实验发现NEAT 1是SIN 3A复合物的兼性组分，揭示了NEAT 1和SIN 3A复合物的机制作用。此外，我们的研究确定了与乳腺癌转移有关的ERa-NEAT 1-FOXN 3/NEAT 1/SIN 3A-GATA 3轴，为FOXN 3的病理生理功能提供了机制性见解。
The pathophysiological function of the forkhead transcription factor FOXN3 remains to be explored. Here we report that FOXN3 is a transcriptional repressor that is physically associated with the SIN3A repressor complex in estrogen receptor-positive (ER+) cells. RNA immunoprecipitation-coupled high-throughput sequencing identified that NEAT1, an estrogen-inducible long noncoding RNA, is required for FOXN3 interactions with the SIN3A complex. ChIP-Seq and deep sequencing of RNA genomic targets revealed that the FOXN3-NEAT1-SIN3A complex represses genes including GATA3 that are critically involved in epithelial-to-mesenchymal transition (EMT). We demonstrated that the FOXN3-NEAT1-SIN3A complex promotes EMT and invasion of breast cancer cells in vitro as well as dissemination and metastasis of breast cancer in vivo. Interestingly, the FOXN3-NEAT1-SIN3A complex transrepresses ER itself, forming a negative-feedback loop in transcription regulation. Elevation of both FOXN3 and NEAT1 expression during breast cancer progression corresponded to diminished GATA3 expression, and high levels of FOXN3 and NEAT1 strongly correlated with higher histological grades and poor prognosis. Our experiments uncovered that NEAT1 is a facultative component of the SIN3A complex, shedding light on the mechanistic actions of NEAT1 and the SIN3A complex. Further, our study identified the ERa-NEAT1-FOXN3/NEAT1/SIN3A-GATA3 axis that is implicated in breast cancer metastasis, providing a mechanistic insight into the pathophysiological function of FOXN3.