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.

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

“…hSETD1A mainly catalyzes H3K4me3 and is thus an important coactivator of gene transcription (27). We previously showed that H3K4me3 and hSETD1A are both upregulated in colorectal cancer cell lines and primary colorectal tumors (26). We also documented that hSETD1A positively impacts the transcription of Wnt/b-catenin target genes, such as MMP7 in colorectal cancer (26).…”

“…We previously showed that H3K4me3 and hSETD1A are both upregulated in colorectal cancer cell lines and primary colorectal tumors (26). We also documented that hSETD1A positively impacts the transcription of Wnt/b-catenin target genes, such as MMP7 in colorectal cancer (26). MMPs are endopeptidases critical in promoting tumor invasiveness by degrading extracellular matrix proteins, including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycans (33).…”

“…ChIP was conducted as previously described (26). Briefly, cells were crosslinked with 1% formaldehyde and 1.5 mmol/L ethylene glycol bis[succinimidylsuccinate] at room temperature.…”

“…We previously showed that hSETD1A and H3K4me3 are upregulated in colorectal carcinoma, and regulate canonical Wnt signaling and cellular proliferation (26). Available evidence suggested that hSETD1A may also function in breast tumorigenesis as gain in human SETD1A gene copy number was detected in 45% (352/782) of breast cancer cases compared with only 6.8% loss in gene copy (53/782; ref.…”

“…For example, trimethylation of Histone H3 at the Lysine 4 residue (H3K4me3) is a wellcharacterized histone mark that is enriched at gene transcriptional start sites (TSS) and is associated with transcriptionally active genes (16)(17)(18)(19). Levels of H3K4me3 are globally and locally altered during different developmental stages of cancer, and can serve as a predictor for disease recurrence (20)(21)(22)(23)(24)(25)(26). It was also recently determined that increased H3K4me3 and decreased H3K27me3 is important for activation of genes linked to proliferation and invasion of breast cancer such as matrix metalloproteinases (MMP), ERBB3, Six1, Cyclin A1, Pim-1, and CSPG4 (14).…”