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The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

Original publication

DOI

10.1101/gr.152942.112

Type

Journal article

Journal

Genome Res

Publication Date

09/2013

Volume

23

Pages

1446 - 1461

Keywords

Animals, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosomal Instability, Chromosomes, Human, Pair 8, Colonic Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, MicroRNAs, Neoplasm Metastasis, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myc, RNA, Long Noncoding, Transcription Factor 7-Like 1 Protein, Transcription, Genetic, Wnt Signaling Pathway