The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L
Abstract
Epithelial cells that lose attachment to the extracellular matrix undergo a specialized form of apoptosis called anoikis. Here, using large-scale RNA interference (RNAi) screening, we find that KDM3A, a histone H3 lysine 9 (H3K9) mono- and di-demethylase, plays a pivotal role in anoikis induction. In attached breast epithelial cells, KDM3A expression is maintained at low levels by integrin signaling. Following detachment, integrin signaling is decreased resulting in increased KDM3A expression. RNAi-mediated knockdown of KDM3A substantially reduces apoptosis following detachment and, conversely, ectopic expression of KDM3A induces cell death in attached cells. We find that KDM3A promotes anoikis through transcriptional activation of BNIP3 and BNIP3L, which encode pro-apoptotic proteins. Using mouse models of breast cancer metastasis we show that knockdown of Kdm3a enhances metastatic potential. Finally, we find defective KDM3A expression in human breast cancer cell lines and tumors. Collectively, our results reveal a novel transcriptional regulatory program that mediates anoikis.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 29, 2016
- Source ID
- 10.7554/elife.16844
Entities
People
- Lihua Julie Zhu
- Michael R Green
- Peter M. Siegel
- Stéphane Gobeil
- Sébastien Tabariès
- Tessa M Simone
- Victoria E Pedanou
Organizations
- Howard Hughes Medical Institute
- Laval University
- McGill University
- National Institutes of Health
- United States Department of Defense
- University of Massachusetts Medical School