Dataset Information

Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications.

ABSTRACT: DCLK1 specifically marks colon/pancreatic cancers in mice, and is expressed by human colon adenocarcinomas (hCRCs). Down-regulation of DCLK1 results in loss of cancer-stem-cells (CSCs), and inhibits spheroidal/xenograft growths from hCRC-cells. The 5'-promoter of DCLK1-gene is reportedly hypermethylated in hCRCs, resulting in loss of expression of DCLK1-transcripts, originating from 5'(?)-promoter (termed DCLK1-L, in here). However, in mouse colon-tumors, 5'-promoter of DCLK1-gene remains unchanged, and DCLK1-L, originating from 5'(?)-promoter, is expressed. We hypothesized that elevated levels of DCLK1-protein in hCRC-cells, may be transcribed/translated from an alternate-promoter. Several in silico and molecular biology approaches were used to test our hypothesis. We report for the first time that majority of hCRCs express short-transcripts of DCLK1 (termed DCLK1-S, in here) from an alternate ?-promoter in IntronV of the gene, while normal-colons mainly express DCLK1-L from 5'(?)-promoter. We additionally report an important role of ?-catenin and TCF4/LEF binding-sites for activating (?)-promoter, while activated NF-?Bp65 (bound to NF-?B-cis-element), activates (?)-promoter in cancer-cells. DCLK1-S expression was examined in a cohort of 92 CRC patients; high-expressors had significantly worse overall-survival compared to low-expressors. Our novel findings' regarding usage of alternate (?)-promoter by hCRCs, suggests that DCLK1-S may represent an important target for preventing/inhibiting colon-cancers, and for eliminating colon-CSCs.

SUBMITTER: O'Connell MR

PROVIDER: S-EPMC4597220 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications.

O'Connell Malaney R MR Sarkar Shubhashish S Luthra Gurinder K GK Okugawa Yoshinaga Y Toiyama Yuji Y Gajjar Aakash H AH Qiu Suimin S Goel Ajay A Singh Pomila P

Scientific reports 20151008

DCLK1 specifically marks colon/pancreatic cancers in mice, and is expressed by human colon adenocarcinomas (hCRCs). Down-regulation of DCLK1 results in loss of cancer-stem-cells (CSCs), and inhibits spheroidal/xenograft growths from hCRC-cells. The 5'-promoter of DCLK1-gene is reportedly hypermethylated in hCRCs, resulting in loss of expression of DCLK1-transcripts, originating from 5'(α)-promoter (termed DCLK1-L, in here). However, in mouse colon-tumors, 5'-promoter of DCLK1-gene remains unchan ...[more]

PMID: 26447334

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Dataset Information

Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications.

Publications

Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications.

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