Stable inheritance of epigenetic states is essential for the maintenance of tissue and cell type specific functions. Aberrations of epigenetic regulation often lead to cancer and other human diseases. Our laboratory is interested in epigenetic regulation by histone demethylases in cancer and stem cells. In particular, we focus on the roles and regulatory mechanisms of histone demethylases from the KDM5 protein family (Figure 1). These enzymes can remove tri- and di- methyl mark from lysine 4 in histone H3 (H3K4me3 and H3K4me2) (figure 1), the epigenetic marks for transcriptionally active chromatin.
We have previously identified KDM5A (also known as JARID1A or RBP2) as one of the first known histone demethylases for H3K4me3. To understand the in vivo function of this enzyme, we generated an Rbp2-/- mouse model (Figure 2), which is the first knockout mouse model for lysine demethylases. We have further showed that KDM5A is critical for tumor formation in several genetically engineered mouse cancer models. We are currently studying how this enzyme contributes to oncogenesis using highly integrated mouse genetic, molecular and cellular biological, and biochemical (Figure 3) approaches. Its functions will be better understood if we combine our findings at the organismal, cellular and molecular levels.
The other research directions of our laboratory focus on another H3K4me3 histone demethylase KDM5B (also known as PLU1 or JARID1B). KDM5B is highly expressed in breast and prostate tumors and is a marker of slow cycling and drug resistant melanoma cells. Similar approaches are undertaken to investigate its roles in cancer. Our current data suggest that these enzymes are potential drug targets for cancer therapy and we have identified specific inhibitors of these enzymes.