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Methods to Discover Alternative Promoter Usage and Transcriptional Regulation of Murine Bcrp1
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Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical

Malaney R O'Connell1, Shubhashish Sarkar1, Gurinder K Luthra2

  • 1Departments of Neuroscience and Cell Biology, UTMB, Galveston, TX.

Scientific Reports
|October 9, 2015
PubMed

Insights

Human colon cancers utilize an alternate DCLK1 promoter (β-promoter) to produce short transcripts (DCLK1-S), unlike normal colons which use the α-promoter. DCLK1-S expression correlates with worse survival in colon cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • DCLK1 (Doublecortin Like Kinase 1) is a marker for colon and pancreatic cancers, and its downregulation impacts cancer stem cells (CSCs).
  • While the 5'(α)-promoter of DCLK1 is hypermethylated in human colorectal adenocarcinomas (hCRCs), leading to loss of DCLK1-L transcripts, it remains unchanged in mouse colon tumors where DCLK1-L is expressed.

Purpose of the Study:

  • To investigate the hypothesis that elevated DCLK1-protein levels in hCRCs originate from an alternate promoter.
  • To identify the specific promoter usage and regulatory mechanisms of DCLK1 in hCRCs versus normal colon tissue.

Main Methods:

  • In silico analysis and molecular biology techniques were employed.
  • Analysis of DCLK1 transcript variants (DCLK1-L and DCLK1-S) and their promoter usage in hCRCs and normal colon tissue.
  • Investigation of transcription factor binding sites (β-catenin, TCF4/LEF, NF-κBp65) and their role in promoter activation.
  • Correlation of DCLK1-S expression levels with patient survival data.

Main Results:

  • Human colorectal adenocarcinomas predominantly express short DCLK1 transcripts (DCLK1-S) from an alternate IntronV β-promoter, whereas normal colons primarily express DCLK1-L from the 5'(α)-promoter.
  • The α-promoter is activated by β-catenin and TCF4/LEF binding sites, while the β-promoter is activated by NF-κBp65 in cancer cells.
  • Elevated DCLK1-S expression in a cohort of 92 CRC patients was significantly associated with poorer overall survival.

Conclusions:

  • hCRCs utilize an alternative β-promoter for DCLK1 transcription, producing DCLK1-S, which differs from the promoter usage in normal colons.
  • DCLK1-S represents a potential therapeutic target for colon cancer treatment and elimination of colon CSCs.
  • NF-κB signaling plays a crucial role in activating the β-promoter in cancer cells, highlighting a key pathway in CRC development.

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