ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis
Yan Chen, … , Yingfei Wang, Weibo Luo
Yan Chen, … , Yingfei Wang, Weibo Luo
Published April 9, 2018
Citation Information: J Clin Invest. 2018;128(5):1937-1955. https://doi.org/10.1172/JCI95089.
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Research Article Oncology

ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis

Abstract

Altered epigenetic reprogramming contributes to breast cancer progression and metastasis. How the epigenetic reader mediates breast cancer progression remains poorly understood. Here, we showed that the epigenetic reader zinc finger MYND-type containing 8 (ZMYND8) is induced by HIF-1 and HIF-2 in breast cancer cells and also upregulated in human breast tumors, and is correlated with poor survival of patients with breast cancer. Genetic deletion of ZMYND8 decreases breast cancer cell colony formation, migration, and invasion in vitro, and inhibits breast tumor growth and metastasis to the lungs in mice. The ZMYND8’s oncogenic effect in breast cancer requires HIF-1 and HIF-2. We further showed that ZMYND8 interacts with HIF-1α and HIF-2α and enhances elongation of the global HIF-induced oncogenic genes by increasing recruitment of BRD4 and subsequent release of paused RNA polymerase II in breast cancer cells. ZMYND8 acetylation at lysines 1007 and 1034 by p300 is required for HIF activation and breast cancer progression and metastasis. These findings uncover a primary epigenetic mechanism of HIF activation and HIF-mediated breast cancer progression, and discover a possible molecular target for the diagnosis and treatment of breast cancer.

Authors

Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Ashwani Kumar, Jennifer E. Wang, Chenliang Wang, Xuan Zou, Chao Xing, Yingfei Wang, Weibo Luo

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Figure 13

A proposed model of ZMYND8 in regulation of HIF transcriptional activity and breast cancer progression and metastasis.

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A proposed model of ZMYND8 in regulation of HIF transcriptional activity...
ZMYND8 is localized at the HREs through H3K14ac and H4K16ac and acetylated at lysines 1007 and 1034 by p300 in breast cancer cells. Acetylated ZMYND8 recruits BRD4 to the HREs to form a HIF transactivation complex. Upon HIF binding to the HRE under hypoxia, ZMYND8/BRD4 are further enriched at the HREs and enhance RNA polymerase II phosphorylation at serine 2 and subsequent transcriptional elongation of the HIF target genes in breast cancer cells, thereby increasing angiogenesis and cell motility and decreasing cell death to promote breast cancer progression and metastasis. ZMYND8 itself is induced by HIF-1 and HIF-2 and thus amplifies HIF activity and HIF-mediated breast cancer progression and metastasis.