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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

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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 11

BRD4 binds to ZMYND8 and is required for ZMYND8-mediated HIF activation in breast cancer cells.

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BRD4 binds to ZMYND8 and is required for ZMYND8-mediated HIF activation ...
(A and B) Co-IP assays of endogenous BRD4 and ZMYND8 in MDA-MB-231 cells (n = 3). (C) Mapping the BRD4 domain binding to ZMYND8. Schematic depiction of FL and domain-deleted BRD4 (top). Co-IP assays of ZMYND8-V5 and FL or truncated FLAG-BRD4 in transfected HEK293T cells (bottom, n = 3). (D) Mapping the ZMYND8 domain binding to BRD4. Co-IP assays of endogenous BRD4 and FL or truncated FLAG-ZMYND8 in HEK293T cells treated with TSA or DMSO (–) for 6 hours (n = 3). (E) RT-qPCR analysis of indicated mRNAs in SC and BRD4-KD1 or -KD2 MDA-MB-231 cells exposed to 20% or 1% O2 for 24 hours in the presence of doxycycline (mean ± SEM, n = 3). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by 2-way ANOVA with Tukey’s t test. (F) HIF luciferase reporter assays in HeLa cells transfected with indicated plasmids and exposed to 20% or 1% O2 for 24 hours in the presence of doxycycline. The FLuc/RLuc activity was determined (mean ± SEM, n = 3). ***P < 0.001, ****P < 0.0001, by 2-way ANOVA with Tukey’s t test. (G) BRD4 ChIP-qPCR assays in parental and ZMYND8-KO2 MDA-MB-231 cells exposed to 20% or 1% O2 for 24 hours (mean ± SEM, n = 3). ***P < 0.001, ****P < 0.0001 by 2-way ANOVA with Sidak’s t test.
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