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Cell Rep. 2016 Jun 21;15(12):2588-96. doi: 10.1016/j.celrep.2016.05.038. Epub 2016 Jun 9.

A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate.

Author information

1
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece.
2
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece; School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
3
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece; DIANA-Lab, Department of Electrical and Computer Engineering, University of Thessaly, 38221 Volos, Greece.
4
Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Greece. Electronic address: hatzis@fleming.gr.

Abstract

The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation, and proliferation in the intestinal epithelium. Constitutive, aberrant activity of the TCF4/β-catenin transcriptional complex is the primary transforming factor in colorectal cancer. We identify a nuclear long non-coding RNA, termed WiNTRLINC1, as a direct target of TCF4/β-catenin in colorectal cancer cells. WiNTRLINC1 positively regulates the expression of its genomic neighbor ASCL2, a transcription factor that controls intestinal stem cell fate. WiNTRLINC1 interacts with TCF4/β-catenin to mediate the juxtaposition of its promoter with the regulatory regions of ASCL2. ASCL2, in turn, regulates WiNTRLINC1 transcriptionally, closing a feedforward regulatory loop that controls stem cell-related gene expression. This regulatory circuitry is highly amplified in colorectal cancer and correlates with increased metastatic potential and decreased patient survival. Our results uncover the interplay between non-coding RNA-mediated regulation and Wnt signaling and point to the diagnostic and therapeutic potential of WiNTRLINC1.

PMID:
27292638
DOI:
10.1016/j.celrep.2016.05.038
[Indexed for MEDLINE]
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