Li Lifang, Liu Xinhua, He Lin, Yang Jianguo, Pei Fei, Li Wanjin, Liu Shumeng, Chen Zhe, Xie Guojia, Xu Bosen, Ting Xia, Zhang Zihan, Jin Tong, Liu Xujun, Zhang Wenting, Yuan Shuai, Yang Ziran, Wu Chongyang, Zhang Yu, Yang Xiaohan, Yi Xia, Liang Jing, Shang Yongfeng, Sun Luyang
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
Nat Commun. 2017 Sep 25;8(1):691. doi: 10.1038/s41467-017-00702-5.
EGFR is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation. However, the molecular mechanism underlying the regulation of EGFR expression remains poorly explored. Here we report that the zinc-finger protein ZNF516 is a transcription repressor. ZNF516 is physically associated with the CtBP/LSD1/CoREST complex and transcriptionally represses a cohort of genes including EGFR that are critically involved in cell proliferation and motility. We demonstrate that the ZNF516-CtBP/LSD1/CoREST complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo. Significantly, low expression of ZNF516 is positively associated with advanced pathological staging and poor survival of breast carcinomas. Our data indicate that ZNF516 is a transcription repressor and a potential suppressor of EGFR, adding to the understanding of EGFR-related breast carcinogenesis and supporting the pursuit of ZNF516 as a potential therapeutic target for breast cancer. EGFR is a well-known oncogene; however, the mechanisms regulating its expression are still unclear. Here, analysing genome-wide chromatin associations, the authors show that in breast cancer cells ZNF516 represses EGFR transcription through the interaction with the CtBP/LSD1/CoREST complex.
表皮生长因子受体（EGFR）是动物发育所必需的，而EGFR的失调与恶性转化密切相关。然而，EGFR表达调控的分子机制仍未得到充分探索。在此，我们报告锌指蛋白ZNF516是一种转录抑制因子。ZNF516与CtBP/LSD1/CoREST复合物存在物理关联，并转录抑制包括EGFR在内的一组基因，这些基因在细胞增殖和迁移中起关键作用。我们证明，ZNF516-CtBP/LSD1/CoREST复合物在体外抑制乳腺癌细胞的增殖和侵袭，并在体内抑制乳腺癌的生长和转移。值得注意的是，ZNF516的低表达与乳腺癌的晚期病理分期和较差的生存率呈正相关。我们的数据表明，ZNF516是一种转录抑制因子，也是EGFR的潜在抑制因子，这有助于加深对EGFR相关乳腺癌发生机制的理解，并支持将ZNF516作为乳腺癌潜在治疗靶点的研究。EGFR是一种著名的致癌基因；然而，调节其表达的机制仍不清楚。在此，通过分析全基因组染色质关联，作者表明在乳腺癌细胞中，ZNF516通过与CtBP/LSD1/CoREST复合物相互作用抑制EGFR转录。
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