title: WHSC1 promotes oncogenesis through regulation of NIMA-related kinase-7 in squamous cell carcinoma of the head and neck.
abstract: Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN. Immunohistochemical analysis of locoregionally advanced SCCHN, dysplastic, and normal epithelial tissue specimens revealed that WHSC1 expression and dimethylation of histone H3 lysine 36 (H3K36me2) were significantly higher in SCCHN tissues than in normal epithelium. Both WHSC1 expression and H3K36me2 levels were significantly correlated with histologic grade. WHSC1 knockdown in multiple SCCHN cell lines resulted in significant growth suppression, induction of apoptosis, and delay of the cell-cycle progression. Immunoblot and immunocytochemical analyses in SCCHN cells demonstrated that WHSC1 induced H3K36me2 and H3K36me3. Microarray expression profile analysis revealed NIMA-related kinase-7 (NEK7) to be a downstream target gene of WHSC1, and chromatin immunoprecipitation (ChIP) assays showed that NEK7 was directly regulated by WHSC1 through H3K36me2. Furthermore, similar to WHSC1, NEK7 knockdown significantly reduced cell-cycle progression, indicating that NEK7 is a key player in the molecular pathway regulated by WHSC1.
  
  
  CONCLUSIONS
  WHSC1 possesses oncogenic functions in SCCHN and represents a potential molecular target for the treatment of SCCHN.
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Saloura
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois. Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Houda
authors.initials: H
authors.lastname: Alachkar
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakakido
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Seiwert
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Mark
authors.initials: M
authors.lastname: Lingen
authors.affiliation: Section of Hematology and Oncology, Northwestern University, Chicago, Illinois.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Licht
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois. rhamamoto@medicine.bsd.uchicago.edu.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; C512685:NEK7 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases