Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
Sci Adv. 2021 Aug 27;7(35). doi: 10.1126/sciadv.abe3771. Print 2021 Aug.
Hypoxia-inducible factors (HIFs) activate transcription of target genes by recruiting coactivators and chromatin-modifying enzymes. Peptidylarginine deiminase 4 (PADI4) catalyzes the deimination of histone arginine residues to citrulline. Here, we demonstrate that PADI4 expression is induced by hypoxia in a HIF-dependent manner in breast cancer and hepatocellular carcinoma cells. PADI4, in turn, is recruited by HIFs to hypoxia response elements (HREs) and is required for HIF target gene transcription. Hypoxia induces histone citrullination at HREs that is PADI4 and HIF dependent. RNA sequencing revealed that almost all HIF target genes in breast cancer cells are PADI4 dependent. PADI4 is required for breast and liver tumor growth and angiogenesis in mice. PADI4 expression is correlated with HIF-1α expression and vascularization in human breast cancer biopsies. Thus, HIF-dependent recruitment of PADI4 to target genes and local histone citrullination are required for transcriptional responses to hypoxia.
缺氧诱导因子 (HIFs) 通过募集共激活因子和染色质修饰酶来激活靶基因的转录。肽基精氨酸脱亚氨酶 4（PADI4）催化组蛋白精氨酸残基向瓜氨酸的脱亚氨作用。在这里，我们证明 PADI4 的表达在乳腺癌和肝癌细胞中依赖 HIF 被低氧诱导。反过来，PADI4 被 HIF 招募到低氧反应元件 (HRE)，并需要 HIF 靶基因转录。低氧诱导 HRE 处的组蛋白瓜氨酸化，这依赖于 PADI4 和 HIF。RNA 测序显示，乳腺癌细胞中几乎所有的 HIF 靶基因都依赖于 PADI4。PADI4 是在小鼠的乳腺癌和肝脏肿瘤生长和血管生成所必需的。PADI4 的表达与人类乳腺癌活检中的 HIF-1α 表达和血管生成相关。因此，HIF 依赖的 PADI4 对靶基因的募集和局部组蛋白瓜氨酸化是对低氧反应所必需的。
