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The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

ABSTRACT: Genome-wide association studies (GWAS) have identified a great number of non-coding risk variants for colorectal cancer (CRC). To date, the majority of these variants have not been functionally studied. Identification of allele-specific transcription factor (TF) binding is of great importance to understand regulatory consequences of such variants. A recently developed proteome-wide analysis of disease-associated SNPs (PWAS) enables identification of DNA-TF interactions in an unbiased fashion. Here, we performed a large-scale PWAS studies to comprehensively characterize TF binding related to CRC, which identified 731 allele-specific TF binding at 116 CRC risk loci. This screen identified rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and consequently increaseing DCLK3 expression through a long-range interaction, which promotes cancer progression through enhancing expression of the genes related to epithelial-to-mesenchymal transition (EMT).

ORGANISM(S): Homo sapiens

PROVIDER: GSE83968 | GEO | 2017/02/15

SECONDARY ACCESSION(S): PRJNA327574

REPOSITORIES: GEO

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Project description:The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (Doublecortin-like kinase 3) which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodeling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including TADA3, a core component of SAGA complex. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodeling in these brain cells, and show that reduced expression of the kinase in Huntington’s disease could render the striatum highly vulnerable to neurodegeneration. Examination of DCLK3 as neuroprotector against mutant huntingtin in vivo and in vitro models.

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The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

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