FOXD3 regulates csc marker, dclk1-s, and invasive potential: Prognostic implications in colon cancer

Shubhashish Sarkar, Malaney R. O'Connell, Yoshinaga Okugawa, Brian S. Lee, Yuji Toiyama, Masato Kusunoki, Robert D. Daboval, Ajay Goel, Pomila Singh

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The 50 (a)-promoter of the human doublecortin-like kinase 1 (DCLK1) gene becomes epigenetically silenced during colon carcinogenesis, resulting in loss of expression of the canonical long(L)-isoform1 (DCLK1-L) in human colon adenocarcinomas (hCRCs). Instead, hCRCs express a short(S)-isoform2 (DCLK1-S) from an alternate (β)-promoter of DCLK1. The current study, examined if the transcriptional activity of the (β)-promoter is suppressed in normal versus cancerous cells. On the basis of in silico and molecular approaches, it was discovered that FOXD3 potently inhibits the transcriptional activity of the (β)-promoter. FOXD3 becomes methylated in human colon cancer cells (hCCC), with loss of FOXD3 expression, allowing expression of the DCLK1(S) variant in hCCCs/hCRCs. Relative levels of FOXD3/DCLK1(S/L) were measured in a cohort of CRC patient specimens (n = 92), in relation to overall survival (OS). Patients expressing high DCLK1(S), with or without low FOXD3, had significantly worse OS compared with patients expressing low DCLK1(S). The relative levels of DCLK1-L did not correlate with OS. In a pilot retrospective study, colon adenomas from high-risk patients (who developed CRCs in <15 years) demonstrated significantly higher staining for DCLK1(S) + significantly lower staining for FOXD3, compared with adenomas from low-risk patients (who remained free of CRCs). Latter results strongly suggest a prognostic value of measuring DCLK1(S)/FOXD3 in adenomas. Overexpression of DCLK1(S), but not DCLK1(L), caused a significant increase in the invasive potential of hCCCs, which may explain worse outcomes for patients with high DCLK1-S-expressing tumors. On the basis of these data, FOXD3 is a potent repressor of DCLK1-S expression in normal cells; loss of FOXD3 in hCCCs/hCRCs allows upregulation of DCLK1-S, imparting a potent invasive potential to the cells.

Original languageEnglish (US)
Pages (from-to)1678-1691
Number of pages14
JournalMolecular Cancer Research
Volume15
Issue number12
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Sarkar, S., O'Connell, M. R., Okugawa, Y., Lee, B. S., Toiyama, Y., Kusunoki, M., Daboval, R. D., Goel, A., & Singh, P. (2017). FOXD3 regulates csc marker, dclk1-s, and invasive potential: Prognostic implications in colon cancer. Molecular Cancer Research, 15(12), 1678-1691. https://doi.org/10.1158/1541-7786.MCR-17-0287