title: Loss of HLTF function promotes intestinal carcinogenesis.
abstract: BACKGROUND
  HLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown.
  
  
  RESULTS
  To address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apcmin/+ mutant background, Hltf- deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf-/-/Apcmin/+ mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apcmin/+ mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased.
  
  
  CONCLUSIONS
  Taken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer.
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, 745 Bannatyne Avenue, Winnipeg MB R3E 0J9, Canada.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sandhu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.forename: Zinnatun
authors.initials: Z
authors.lastname: Nabi
authors.forename: Mojgan
authors.initials: M
authors.lastname: Rastegar
authors.forename: Sam
authors.initials: S
authors.lastname: Kung
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D014157:Transcription Factors