title: Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1.
abstract: 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.
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: John D
authors.initials: JD
authors.lastname: Kelly
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.forename: Masahi
authors.initials: M
authors.lastname: Takawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshimatsu
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Helen I
authors.initials: HI
authors.lastname: Field
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.forename: Bruce Aj
authors.initials: BA
authors.lastname: Ponder
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001381:Azepines / Q000494:pharmacology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000098563:Seven in Absentia Proteins
chemical_list: D001381:Azepines; C518299:BIX 01294; D006649:Histocompatibility Antigens; D009687:Nuclear Proteins; D011799:Quinazolines; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins