Histone Citrullination by PADI4 is Required for HIF-dependent Transcriptional Responses to Hypoxia and Tumor Vascularization

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Aug 28

PMID 34452909

Citations 28

Authors

Yufeng Wang

Yajing Lyu

Kangsheng Tu

Qiuran Xu

Yongkang Yang

Shaima Salman

Nguyet Le

Haiquan Lu

Chelsey Chen

Yayun Zhu

Ru Wang

Qingguang Liu

Gregg L Semenza

Affiliations

Soon will be listed here.

Abstract

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.

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