@article{e752adbd4fe140ad958302ce493c4ef3,
title = "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.",
author = "Yan Chen and Bo Zhang and Lei Bao and Lai Jin and Mingming Yang and Yan Peng and Ashwani Kumar and Wang, {Jennifer E.} and Chenliang Wang and Xuan Zou and Chao Xing and Yingfei Wang and Weibo Luo",
note = "Funding Information: We thank Gregg L. Semenza (Johns Hopkins) for HeLa, HEK293T, MCF-7, T47D, HCC1954, and SUM159 cells; Rolf Brekken (UT Southwestern) for MDA-MB-231 cells; Cheng-Ming Chiang (UT Southwestern) for BRD4 plasmids and purified p300, PCAF, and GCN5 proteins; Kyle Miller (The University of Texas at Austin) for SFB-ZMYND8 plasmids; and Lei Guo (UT Southwestern) for generation of FLAG–HIF-2α plasmid. We also thank the UTSW Cancer Center Tissue Resource for assistance with immunohistochemistry (supported by NCI Cancer Center grant P30CA142543), the UTSW Next Generation Sequencing Core for assistance with RNA-seq and ChIP-seq, and the UTSW Pathology digital imaging core for TMA slide scanning. We are grateful to Carole Baas (Dallas, Texas, USA) for comments on the manuscript. This work was supported by grants from Susan G. Komen (CCR16376227), NIH (R00CA168746), the Cancer Prevention & Research Institute of Texas (CPRIT, RR140036), and the American Cancer Society/ UTSW Simmons Cancer Center (ACS-IRG-02-196) to WL, and grants from NIH (R00NS078049, R35GM124693) to YW. CX was partially supported by NIH grant UL1TR001105. WL is a CPRIT Scholar in Cancer Research. Publisher Copyright: {\textcopyright} 2018 Academic Press. All rights reserved.",
year = "2018",
month = may,
day = "1",
doi = "10.1172/JCI95089",
language = "English (US)",
volume = "128",
pages = "1937--1955",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",
}