Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the Wnt pathway.
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 G(2)/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.
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Tokyo, Japan.
Gouji
G
Toyokawa
Hyun-Soo
HS
Cho
Ken
K
Masuda
Yuka
Y
Yamane
Masanori
M
Yoshimatsu
Shinya
S
Hayami
Masashi
M
Takawa
Yukiko
Y
Iwai
Yataro
Y
Daigo
Eiju
E
Tsuchiya
Tatsuhiko
T
Tsunoda
Helen I
HI
Field
John D
JD
Kelly
David E
DE
Neal
Yoshihiko
Y
Maehara
Bruce Aj
BA
Ponder
Yusuke
Y
Nakamura
Ryuji
R
Hamamoto
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D056945:Hep G2 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D006657:Histones; D012097:Repressor Proteins; D051176:beta Catenin; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human