Abstract
Epigenetics is the study of transcriptional and physiological trait variations that do not involve changes in the DNA sequence. DNA methylation and post-translational modification in the histone tail are major mechanisms that produce such changes. One of histone modifications, methylation/demethylation, is controlled by histone methyltransferase and histone demethylase has been recently studied. Dysregulation of histone methylation/demethylation is found to be associated with various types of cancer. The major type of lysine demethylase (KDM) consists of Jumonji-C (JmjC) domain (KDM2‒KDM8) and requires 2-oxoglutarate and Fe(II) as cofactors to remove the methyl moiety from the histone tail. Of those, KDM4B, a member of the KDM4 family can specifically remove the methyl group from H3K9me3/me2 and H3K36me3/me2. KDM4B are overexpressed in many types of cancer including gastric cancer, renal cancer, colon cancer, breast cancer and prostate cancer. In prostate cancer, KDM4B is a co-activator of androgen receptor (AR) to stimulate cell growth. Given the important role of AR in prostate carcinogenesis, we propose KDM4B as a useful target protein. In this study, we aim to discover natural compounds that inhibit KDM4B based on a structure-guided approach. We have successfully identified a compound M2 with IC50 = 12.2 ± 1.6 μM, Ki= 2.72 μM. M2 exhibits a competitive inhibition mode toward KDM4B. M2 also shows inhibition against other members of the KDM4 family but not against PHF8. In cell-based experiment, M2 had cytoxicity in AR-dependent (LNCaP) as well as AR-independent prostate cancer cells (CWR22Rv1, LNCaP C4-2B and PC-3). Addition of M2 in LNCaP and CWR22Rv1 cells led to the increase of H3K9m3 signal. Together, M2 is a specific KDM4 inhibitor and shows anti-prostate cancer effect. Future work is to derive M2-based compounds with higher specificity and potency.