title: hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells.
abstract: hSETD1A is a member of the trithorax (TrxG) family of histone methyltransferases (HMT) that methylate H3K4 at promoters of active genes. Although misregulation of mixed lineage leukemia (MLL) family proteins has been associated with acute leukemia, the role of hSETD1A in cancer remains unknown. In this study, we report that hSETD1A and its associated H3K4me3 are upregulated in human colorectal cancer cells and patient samples. Depletion of hSETD1A inhibits colorectal cancer cell growth, colony formation, and tumor engraftment. Genome-wide expression profiling of colorectal cancer cells reveals that approximately 50% of Wnt/β-catenin target genes are affected by the hSETD1A knockdown. We further demonstrate that hSETD1A is recruited to promoters of those Wnt signaling target genes through its interaction with β-catenin, a master regulator of the Wnt signaling pathway. The recruitment of the hSETD1A HMT complex confers promoter-associated H3K4me3 that leads to assembly of transcription preinitiation complex and transcriptional activation. Furthermore, the expression levels of hSETD1A are positively correlated with H3K4me3 enrichment at the promoters of Wnt/β-catenin target genes and the aberrant activation of these genes in human colorectal cancer. These results provide new biologic and mechanistic insights into the cooperative role of hSETD1A and β-catenin in regulation of Wnt target genes as well as in colorectal cancer cell growth in vitro and in vivo.
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Microbiology and Molecular Genetics, Medicine, Anatomy and Cell Biology; and Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Tal
authors.initials: T
authors.lastname: Salz
authors.forename: Guangyao
authors.initials: G
authors.lastname: Li
authors.forename: Frederic
authors.initials: F
authors.lastname: Kaye
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D047368:Tumor Burden; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D006657:Histones; D051153:Wnt Proteins; D051176:beta Catenin; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human