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 3

ZMYND8 depletion suppresses tumorigenic potential of breast cancer cells in vitro.

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ZMYND8 depletion suppresses tumorigenic potential of breast cancer cells...
(A and B) Colony formation of parental and ZMYND8-KO1 or -KO2 MDA-MB-231 cells cultured under 20% or 1% O2 for 12 days. Representative images from 3 experiments are shown in A. Quantification of colony numbers is shown in B (mean ± SEM, n = 3). ####P < 0.0001 versus parental at 20% O2, **P < 0.01, ****P < 0.0001 versus parental, by 2-way ANOVA with Tukey’s t test. (C–F) Migration (C and D) and invasion (E and F) of SC and ZMYND8-KD1 or -KD2 MDA-MB-231 cells under 20% or 1% O2. Representative images from 3 experiments are shown in C and E. Migrated and invaded cell numbers are quantified in D and F, respectively (mean ± SEM, n = 3). ####P < 0.0001 versus SC at 20% O2, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus SC, by 2-way ANOVA with Tukey’s t test. Scale bar, 100 μm.