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 ERα-NEAT1-FOXN3/NEAT1/SIN3A-GATA3 axis that is implicated in breast cancer metastasis, providing a mechanistic insight into the pathophysiological function of FOXN3.

中文翻译：

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FOXN3-NEAT1-SIN3A 抑制复合物促进激素反应性乳腺癌的进展

叉头转录因子 FOXN3 的病理生理功能仍有待探索。在这里，我们报告 FOXN3 是一种转录抑制因子，与雌激素受体阳性 (ER ⁺ ) 细胞中的 SIN3A 抑制因子复合物物理相关。RNA 免疫沉淀偶联高通量测序发现 NEAT1，一种雌激素诱导的长链非编码 RNA，是 FOXN3 与 SIN3A 复合物相互作用所必需的。芯片序列和 RNA 基因组目标的深度测序显示 FOXN3-NEAT1-SIN3A 复合物抑制包括GATA3在内的基因与上皮间质转化 (EMT) 密切相关。我们证明了 FOXN3-NEAT1-SIN3A 复合物在体外促进 EMT 和乳腺癌细胞的侵袭以及在体内乳腺癌的传播和转移。有趣的是，FOXN3-NEAT1-SIN3A 复合物反式抑制 ER 本身，在转录调控中形成负反馈回路。在乳腺癌进展期间 FOXN3 和 NEAT1 表达的升高对应于 GATA3 表达的减少，并且 FOXN3 和 NEAT1 的高水平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 NEAT1 是 SIN3A 复合物的兼性成分，揭示了 NEAT1 和 SIN3A 复合物的机械作用。更远，