title: Epigenetic regulation of humanDCLK-1gene during colon-carcinogenesis: clinical and mechanistic implications.
abstract: Colorectal carcinogenesis is a multi-step process. While ~25% of colorectal cancers (CRCs) arise in patients with a family history (genetic predisposition), ~75% of CRCs are due to age-associated accumulation of epigenetic alterations which can result in the suppression of key tumor suppressor genes leading to mutations and activation of oncogenic pathways. Sporadic colon-carcinogenesis is facilitated by many molecular pathways of genomic instability which include chromosomal instability (CIN), micro-satellite instability (MSI) and CpG island methylator phenotype (CIMP), leading towards loss of homeostasis and onset of neoplastic transformation. The unopposed activation of Wnt/β-catenin pathways, either due to loss of APC function or up-regulation of related stimulatory pathways, results in unopposed hyperproliferation of colonic crypts, considered the single most important risk factor for colon carcinogenesis. Hypermethylation of CpG islands within the promoters of specific genes can potentially inactivate DNA repair genes and/or critical tumor suppressor genes. Recently, CpG methylation of the 5' promoter of human (h)DCLK1gene was reported in many human epithelial cancers, including colorectal cancers (CRCs), resulting in the loss of expression of the canonical long isoform of DCLK1 (DCLK1-L) in hCRCs. Instead, a shorter isoform of DCLK1 (DCLK1-S) was discovered to be expressed in hCRCs, from an alternate β promoter ofDCLKL1-gene; the clinical and biological implications of these novel findings, in relation to recent publications is discussed.
authors: Neuroscience and Cell Biology Department, University of Texas and Medical Branch, Galveston, TX, USA.
authors: Pomila
authors: P
authors: Singh
authors: Neuroscience and Cell Biology Department, University of Texas and Medical Branch, Galveston, TX, USA.
authors: Malaney
authors: M
authors: O'Connell
authors: Neuroscience and Cell Biology Department, University of Texas and Medical Branch, Galveston, TX, USA.
authors: Sarkar
authors: S
authors: Shubhashish
keywords: 5’(α) and IntronV(β) promoters of hDCLK1-gene; Cancer stem cells (CSCs); DCLK1-long isoform (DCLK1-L); colorectal cancers (CRCs); short isoform of DCLK1 (DCLK1-S)