ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer.
ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer.
复制标题
ZHX2促进三阴性乳腺癌中的HIF 1 α致癌信号传导
DOI：
10.7554/elife.70412
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发表时间：
2021-11-15
期刊：
影响因子：
7.7
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Fang W;Liao C;Shi R;Simon JM;Ptacek TS;Zurlo G;Ye Y;Han L;Fan C;Bao L;Ortiz CL;Lin HR;Manocha U;Luo W;Peng Y;Kim WY;Yang LW;Zhang Q
三阴性乳腺癌（TNBC）是一种侵袭性和高致死性的疾病，这保证了迫切需要确定新的治疗靶点。我们显示锌指和同源异型盒2（ZHX 2）在TNBC细胞系和患者中扩增或过表达。在功能上，ZHX 2的消耗抑制体外TNBC细胞生长和侵袭、原位肿瘤生长和体内自发性肺转移。在机制上，ZHX 2与缺氧诱导因子（HIF）家族成员结合，并在TNBC中正向调节HIF 1 α活性。整合ChIP-seq和基因表达谱分析表明，ZHX 2与HIF 1 α共同占据由H3 K4 me 3和H3 K27 ac标记的转录活性启动子，从而促进基因表达。在已鉴定的ZHX 2和HIF 1 α共调控基因中，AP 2B 1、COX 20、KDM 3A或PTGES 3L的过表达可通过ZHX 2耗竭部分挽救TNBC细胞的生长缺陷，表明这些下游靶点以累积的方式促进ZHX 2的致癌作用。此外，ZHX 2上的多个残基（R491、R581和R674）在调节其表型中是重要的，这与它们在TNBC细胞中控制ZHX 2转录活性的作用相对应。这些研究证实，ZHX 2激活致癌HIF 1 α信号传导，因此可作为TNBC的潜在治疗靶点。
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth, and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia-inducible factor (HIF) family members and positively regulated HIF1α activity in TNBC. Integrated ChIP-seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1α coregulated genes, overexpression of AP2B1, COX20, KDM3A, or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581, and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.
影响因子：
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作者：
Bird LE;Ren J;Nettleship JE;Folkers GE;Owens RJ;Stammers DK
通讯作者：
Stammers DK