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

Gouji Toyokawa, Hyun Soo Cho, Ken Masuda, Yuka Yamane, Masanori Yoshimatsu, Shinya Hayami, Masashi Takawa, Yukiko Iwai, Yataro Daigo, Eiju Tsuchiya, Tatsuhiko Tsunoda, Helen I. Field, John D. Kelly, David E. Neal, Yoshihiko Maehara, Bruce A.J. Ponder, Yusuke Nakamura, Ryuji Hamamoto

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69 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)887-898
Number of pages12
JournalNeoplasia
Volume13
Issue number10
DOIs
Publication statusPublished - Oct 2011

All Science Journal Classification (ASJC) codes

  • Cancer Research

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    Toyokawa, G., Cho, H. S., Masuda, K., Yamane, Y., Yoshimatsu, M., Hayami, S., Takawa, M., Iwai, Y., Daigo, Y., Tsuchiya, E., Tsunoda, T., Field, H. I., Kelly, J. D., Neal, D. E., Maehara, Y., Ponder, B. A. J., Nakamura, Y., & Hamamoto, R. (2011). Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the WNT pathway. Neoplasia, 13(10), 887-898. https://doi.org/10.1593/neo.11048