Invasive growth and apoptosis resistance of breast cancer cells are associated with metastasis and disease relapse. Here we identified that the lysine-specific demethylase KDM3A played a dual role in breast cancer cell invasion and apoptosis by demethylating histone and the non-histone protein p53, respectively. While inducing pro-invasive genes by erasing repressive histone H3 lysine 9 methylation, KDM3A promotes chemoresistance by demethylating p53. KDM3A suppressed pro-apoptotic functions of p53 by erasing p53-K372me1, as this methylation is crucial for the stability of chromatin-bound p53. Unexpectedly, depletion of KDM3A was capable of reactivating mutated p53 to induce the expression of pro-apoptotic genes in breast cancer with mutant p53. Moreover, KDM3A knockdown also potently inhibited tumorigenic potentials of breast cancer stem-like cells and rendered them sensitive to apoptosis induced by chemotherapeutic drugs. Taken together, our results suggest that KDM3A might be a potential therapeutic target for human breast cancer treatment and prevention.
