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The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer
Wanjin Li, … , Jing Liang, Yongfeng Shang
Wanjin Li, … , Jing Liang, Yongfeng Shang
Published August 14, 2017
Citation Information: J Clin Invest. 2017;127(9):3421-3440. https://doi.org/10.1172/JCI94233.
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Research Article Cell biology Endocrinology Article has an altmetric score of 2

The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer

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Abstract

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.

Authors

Wanjin Li, Zihan Zhang, Xinhua Liu, Xiao Cheng, Yi Zhang, Xiao Han, Yu Zhang, Shumeng Liu, Jianguo Yang, Bosen Xu, Lin He, Luyang Sun, Jing Liang, Yongfeng Shang

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Figure 2

NEAT1 is required for the interaction of FOXN3 with the SIN3A complex.

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NEAT1 is required for the interaction of FOXN3 with the SIN3A complex.
(...
(A) Venn diagrams of FOXN3 iRIP-Seq results for potential lncRNAs (left). The RNA contact sites (RCSs) that represent the most frequent tags are mapped to the sequences of NEAT1 and MALAT1 (right). NEAT1 fragment used for in vitro RNA pull-down is indicated. (B) RIP-qPCR verification of the iRIP-Seq results with antibodies against the indicated proteins in MCF-7 cells. Error bars represent mean ± SD for triplicate experiments (*P < 0.05, **P < 0.01; t test). (C) Scatter plot of microarray profiling of lncRNA expression in the indicated cell lines. (D) qPCR analysis of the expression of NEAT1 and MALAT1 in the indicated cell lines. Error bars represent mean ± SD for triplicate experiments (**P < 0.01, 1-way ANOVA). (E) RIP-qPCR analysis of FOXN3 RIP or SIN3A RIP for the enrichment of NEAT1 and MALAT1 in MCF-7 and T-47D cells. Error bars represent mean ± SD for triplicate experiments (*P < 0.05, t test). (F) IP in MCF-7 cells depleted with NEAT1 or MALAT1 using anti-FOXN3 followed by IB with anti-SIN3A (top) or IP with anti-HDAC1, anti-HDAC2, or anti-SIN3A followed by IB with the indicated antibodies (bottom left). Cellular lysates from NEAT1-overexpressed MDA-MB-231 cells were immunoprecipitated with anti-FOXN3 followed by IB with anti-SIN3A (bottom right). Knockdown efficiency was verified by qPCR. (G) Reporter assays in NEAT1- or MALAT1-depleted MCF-7 cells. Knockdown efficiency was verified by qPCR. Error bars represent mean ± SD for triplicate experiments (**P < 0.01, 2-way ANOVA). (H) Wild-type or ERα-depleted MCF-7 cells were deprived of steroids before treatment with E2 for the indicated times. Total RNAs were extracted for qPCR analysis of the expression of NEAT1. Error bars represent mean ± SD for triplicate experiments (**P < 0.01, 1-way ANOVA).

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