JMJD2A is a transcriptional cofactor and enzyme that catalyzes demethylation of histone H3 lysines 9 and 36 and is overexpressed in human tumors, but its role in oncogenesis remains unclear. Here, we show that JMJD2A interacts with the tumor suppressor p53 both in vitro and in HCT116 colon cancer cells. Chromatin immunoprecipitation assays demonstrated that JMJD2A was recruited together with p53 to the promoter of the p21 cell cycle inhibitor upon stimulation with the DNA damaging agent, adriamycin. Downregulation of JMJD2A resulted in increased expression of p21 and of the pro‐apoptotic Puma protein, whereas levels of the anti‐apoptotic Bcl‐2 protein were decreased. Furthermore, JMJD2A knock‐down led to reduced HCT116, DLD‐1 and HT‐29 colon cancer cell proliferation, while overexpression of JMJD2A enhanced HCT116 proliferation in low serum media. Finally, JMJD2A depletion induced apoptosis in HCT116 cells and this effect was less pronounced in the absence of p53. Collectively, these data indicate that JMJD2A is a novel promoter of colon cancer cell proliferation and survival, which mediates its effects in p53‐dependent and ‐independent ways. JMJD2A may therefore be a valid target to sensitize tumor cells to chemotherapy‐induced cell death and growth suppression. J. Cell. Biochem. 113: 1368–1376, 2012. © 2011 Wiley Periodicals, Inc.