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A number of histone methyltransferases have been identified and biochemically characterized, but the pathologic roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays important roles in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNA targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Cell cycle analysis by flow cytometry indicated that knockdown of WHSC1 decreased the cell population of cancer cells at the S phase while increasing that at the G2/M phase. WHSC1 interacts with some proteins related to the WNT pathway including β-catenin and transcriptionally regulates CCND1, the target gene of the β-catenin/Tcf-4 complex, through histone H3 at lysine 36 trimethylation. This is a novel mechanism for WNT pathway dysregulation in human carcinogenesis, mediated by the epigenetic regulation of histone H3. Because expression levels of WHSC1 are significantly low in most normal tissue types, it should be feasible to develop specific and selective inhibitors targeting the enzyme as antitumor agents that have a minimal risk of adverse reaction.

EHMT2 is a histone lysine methyltransferase localized in euchromatin regions and acting as a corepressor for specific transcription factors. Although the role of EHMT2 in transcriptional regulation has been well documented, the pathologic consequences of its dysfunction in human disease have not been well understood. Here, we describe important roles of EHMT2 in human carcinogenesis. Expression levels of EHMT2 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (P < .0001) in real-time polymerase chain reaction analysis. Complementary DNA microarray analysis also revealed its overexpression in various types of cancer. The reduction of EHMT2 expression by small interfering RNAs resulted in the suppression of the growth of cancer cells and possibly caused apoptotic cell death in cancer cells. Importantly, we show that EHMT2 can suppress transcription of the SIAH1 gene by binding to its promoter region (-293 to +51) and by methylating lysine 9 of histone H3. Furthermore, an EHMT2-specific inhibitor, BIX-01294, significantly suppressed the growth of cancer cells. Our results suggest that dysregulation of EHMT2 plays an important role in the growth regulation of cancer cells, and further functional studies may affirm the importance of EHMT2 as a promising therapeutic target for various types of cancer.