The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L
- Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
- Université Laval, Canada
- McGill University, Canada
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.
Data availability
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The histone H3K9 demethylase KDM3A promotes anoikis through transcriptional activation of pro-apoptotic genes BNIP3 and BNIP3LPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE80144).
Article and author information
Author details
Funding
National Institutes of Health (R01GM033977)
- Michael R Green
Howard Hughes Medical Institute (68101)
- Michael R Green
U.S. Department of Defense (BC060871)
- Michael R Green
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Massachusetts Medical School (A-2300) and McGill University. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Human subjects: This study was approved by the institutional review boards at the University of Massachusetts Medical School (UMMS) and the Mayo Clinic. Consent to publish is not necessary as all patient samples were de-identified.
Copyright
© 2016, Pedanou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
