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. DOI: http://dx.doi.org/10.7554/eLife.16844.001, eLife digest Epithelial cells line the inside of blood vessels, intestines and other organs throughout the body. Any epithelial cells that become detached from their natural surroundings die by a process called anoikis (a Greek word meaning “being without a home”). This process has an important role in preventing cancer from spreading around the body because it eliminates cells that are not in their proper environment. However, some cancers that start from epithelial cells, such as breast cancer, develop resistance to anoikis. Gaining a better understanding of the cellular factors that regulate anoikis, and how resistance develops, may reveal new drug targets for the treatment of breast cancer. Previous studies found proteins called BIM and BMF promote anoikis by inducing cell suicide. However, it is possible that other factors can also promote this process in different ways. Pedanou et al. performed a large-scale genetic screen in human breast epithelial cells and identified several new factors that promote anoikis. Inside our cells, DNA is packaged around proteins called histones, which can influence whether a gene is switched on or off. One of the factors Pedanou et al. identified is a protein called KDM3A that can remove small chemical groups (known as methyl groups) from histones – a process that is known to switch on genes. Further experiments show that epithelial cells in their natural surroundings only produce low levels of KDM3A, but that the levels of this protein increase if these cells become detached. This promotes anoikis by activating two genes called BNIP3 and BNIP3L that induce cell suicide. However, KDM3A levels are low in human breast cancers, which suggests that these cancers become resistant to anoikis by preventing increases in KDM3A production. Using a mouse model of breast cancer, Pedanou et al. found that switching off KDM3A in cancer cells increases their ability to move around the body. Collectively, these findings reveal a new mechanism that triggers anoikis in normal breast epithelial cells and is disabled during breast cancer development. Future challenges are to identify factors that directly regulate the production of KDM3A, and to understand how these factors are manipulated in breast cancer cells to cause anoikis resistance. DOI: http://dx.doi.org/10.7554/eLife.16844.002