ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1937-1955
Number of pages19
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
StatePublished - May 1 2018

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Zinc Fingers
Acetylation
Breast Neoplasms
Neoplasm Metastasis
Epigenomics
RNA Polymerase II
Lysine

ASJC Scopus subject areas

  • Medicine(all)

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ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis. / Chen, Yan; Zhang, Bo; Bao, Lei; Jin, Lai; Yang, Mingming; Peng, Yan; Kumar, Ashwani; Wang, Jennifer E.; Wang, Chenliang; Zou, Xuan; Xing, Chao; Wang, Yingfei; Luo, Weibo.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1937-1955.

Research output: Contribution to journalArticle

Chen, Y, Zhang, B, Bao, L, Jin, L, Yang, M, Peng, Y, Kumar, A, Wang, JE, Wang, C, Zou, X, Xing, C, Wang, Y & Luo, W 2018, 'ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis', Journal of Clinical Investigation, vol. 128, no. 5, pp. 1937-1955. https://doi.org/10.1172/JCI95089
Chen, Yan ; Zhang, Bo ; Bao, Lei ; Jin, Lai ; Yang, Mingming ; Peng, Yan ; Kumar, Ashwani ; Wang, Jennifer E. ; Wang, Chenliang ; Zou, Xuan ; Xing, Chao ; Wang, Yingfei ; Luo, Weibo. / ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1937-1955.
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