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ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis
- Source :
- Journal of Clinical Investigation. 128:1937-1955
- Publication Year :
- 2018
- Publisher :
- American Society for Clinical Investigation, 2018.
-
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.
- Subjects :
- 0301 basic medicine
BRD4
Breast Neoplasms
Cell Cycle Proteins
Mice, SCID
Metastasis
03 medical and health sciences
0302 clinical medicine
Breast cancer
Downregulation and upregulation
Basic Helix-Loop-Helix Transcription Factors
medicine
Animals
Humans
Epigenetics
Neoplasm Metastasis
skin and connective tissue diseases
Zinc finger
business.industry
Tumor Suppressor Proteins
Nuclear Proteins
Acetylation
General Medicine
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
HEK293 Cells
030104 developmental biology
030220 oncology & carcinogenesis
MCF-7 Cells
Cancer research
Female
RNA Polymerase II
business
Reprogramming
HeLa Cells
Transcription Factors
Research Article
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 128
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....e955e7ca05540ffce0c9eb65173c3bb2