CHD4 Promotes Breast Cancer Progression as a Coactivator of Hypoxia-Inducible Factors.
CHD4 Promotes Breast Cancer Progression as a Coactivator of Hypoxia-Inducible Factors.
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DOI：
10.1158/0008-5472.can-20-1049
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发表时间：
2020-09-15
期刊：
影响因子：
11.2
通讯作者：
Luo W
中科院分区：
文献类型：
--
作者：
Wang Y;Chen Y;Bao L;Zhang B;Wang JE;Kumar A;Xing C;Wang Y;Luo W
低氧诱导因子（HIF）靶基因募集RNA聚合酶II是HIF介导的转激活的先决条件。然而，这种招募的潜在机制尚不清楚。在这里，我们报道了染色质结构域解旋酶dna结合蛋白4 （CHD4）与HIF-1和HIF-2的α和β亚基物理相互作用，并增强hif驱动的转录程序，促进乳腺癌的进展。HIF-1/2α缺失可抑制chd4介导的小鼠乳腺肿瘤生长。在正常缺氧条件下的乳腺癌细胞中，HIF靶基因启动子处CHD4的富集通过p300增加了RNA聚合酶II的负载。缺氧进一步促进CHD4通过HIF-1/2α与染色质结合，CHD4反过来增强HIF-1α的募集，导致HIF靶基因转录。CHD4在人乳腺肿瘤中上调并与HIF靶基因表达相关；CHD4和其他已知的HIF共激活因子在人类乳腺肿瘤中的上调是相互排斥的。此外，CHD4与乳腺癌患者的总生存率较低有关。总之，这些发现揭示了HIF调控乳腺癌的一种新的基本机制，具有临床意义。
Recruitment of RNA polymerase II to hypoxia-inducible factor (HIF) target genes under normoxia is a prerequisite for HIF-mediated transactivation. However, the underlying mechanism of this recruitment remains unknown. Here we report that chromodomain helicase DNA-binding protein 4 (CHD4) physically interacts with αand β subunits of HIF-1 and HIF-2 and enhances HIF-driven transcriptional programs to promote breast cancer progression. Loss of HIF-1/2α abolished CHD4-mediated breast tumor growth in mice. In breast cancer cells under normoxia, CHD4 enrichment at HIF target gene promoters increased RNA polymerase II loading through p300. Hypoxia further promoted CHD4 binding to the chromatin via HIF-1/2α, where CHD4 in turn enhanced recruitment of HIF-1α, leading to HIF target gene transcription. CHD4 was upregulated and correlated with HIF target gene expression in human breast tumors; upregulation of CHD4 and other known HIF coactivators in human breast tumors was mutually exclusive. Furthermore, CHD4 was associated with poor overall survival of breast cancer patients. Collectively, these findings reveal a new fundamental mechanism of HIF regulation in breast cancer, which has clinical relevance.