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.
Highlights
Epithelial cells that lose attachment to the extracellular matrix (ECM), or attach to an inappropriate ECM, undergo a specialized form of apoptosis called anoikis
Anoikis is suppressed by integrin signaling, which functions through focal adhesion kinase (FAK), an activator of the RAF/MEK/ERK
The screen was performed in MCF10A cells, an immortalized but non-transformed human breast epithelial cell line that has been frequently used to study anoikis
Summary
Epithelial cells that lose attachment to the extracellular matrix (ECM), or attach to an inappropriate ECM, undergo a specialized form of apoptosis called anoikis. The qRT-PCR analysis of Figure 2B shows that an increase in KDM3A expression following detachment was detected at the mRNA level. Treatment of MCF10A cells with a FAK inhibitor increased the levels of KDM3A protein (Figure 2D) and mRNA (Figure 2–figure supplement 1A).
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