Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms

Clinical Implications

Malaney R. Oconnell, Shubhashish Sarkar, Gurinder Luthra, Yoshinaga Okugawa, Yuji Toiyama, Aakash Gajjar, Suimin Qiu, Ajay Goel, Pomila Singh

Research output: Contribution to journalArticle

25 Citations (Scopus)

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′(α)-promoter (termed DCLK1-L, in here). However, in mouse colon-tumors, 5′-promoter of DCLK1-gene remains unchanged, and DCLK1-L, originating from 5′(α)-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 β-promoter in IntronV of the gene, while normal-colons mainly express DCLK1-L from 5′(α)-promoter. We additionally report an important role of β-catenin and TCF4/LEF binding-sites for activating (α)-promoter, while activated NF-Bp65 (bound to NF-B-cis-element), activates (β)-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 findingsregarding usage of alternate (β)-promoter by hCRCs, suggests that DCLK1-S may represent an important target for preventing/inhibiting colon-cancers, and for eliminating colon-CSCs.

Original languageEnglish (US)
Article number14983
JournalScientific Reports
Volume5
DOIs
StatePublished - Oct 8 2015

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Epigenomics
Colonic Neoplasms
Protein Isoforms
Colon
Adenocarcinoma
Neoplastic Stem Cells
Genes
Catenins
Pancreatic Neoplasms
Heterografts
Carcinogens
Computer Simulation
Molecular Biology
Down-Regulation
Binding Sites
Survival
Growth
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms : Clinical Implications. / Oconnell, Malaney R.; Sarkar, Shubhashish; Luthra, Gurinder; Okugawa, Yoshinaga; Toiyama, Yuji; Gajjar, Aakash; Qiu, Suimin; Goel, Ajay; Singh, Pomila.

In: Scientific Reports, Vol. 5, 14983, 08.10.2015.

Research output: Contribution to journalArticle

Oconnell, Malaney R. ; Sarkar, Shubhashish ; Luthra, Gurinder ; Okugawa, Yoshinaga ; Toiyama, Yuji ; Gajjar, Aakash ; Qiu, Suimin ; Goel, Ajay ; Singh, Pomila. / Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms : Clinical Implications. In: Scientific Reports. 2015 ; Vol. 5.
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