Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the Wnt pathway.

[wolf-hirschhorn syndrome]

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 (WHSC 1 ) 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 WHSC 1 expression in bladder and lung cancer cells at the protein level . Treatment of cancer cell lines with small interfering RNA targeting WHSC 1 significantly knocked down its expression and resulted in the suppression of proliferation . Cell cycle analysis by flow cytometry indicated that knockdown of WHSC 1 decreased the cell population of cancer cells at the S phase while increasing that at the G (2 )/M phase . WHSC 1 interacts with some proteins related to the WNT pathway including β-catenin and transcriptionally regulates CCND 1 , the target gene of the β-catenin /Tcf-4 complex , through histone H 3 at lysine 36 trimethylation . This is a novel mechanism for WNT pathway dysregulation in human carcinogenesis , mediated by the epigenetic regulation of histone H 3 . Because expression levels of WHSC 1 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 .