Journal
ONCOGENE
Volume 39, Issue 6, Pages 1347-1360Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-019-1055-4
Keywords
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Funding
- National Natural Science Foundation of China [81421001, 81530072, 81320108024, 81830081, 81522008, 81874159, 81871901, 31371273, 81770165]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [201268]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant [20152512, 20161309]
- Chenxing Project of Shanghai Jiao Tong University
- Shu Guang project [17CG17]
- Program for Professor of Special Appointment (2015 Youth Eastern Scholar) at Shanghai Institutions of Higher Learning [QD2015003]
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Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.
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