ASBEL–TCF3 complex is required for the tumorigenicity of colorectal cancer cells

Abstract

<p id="d6499388e254">Wnt/β-catenin signaling plays crucial roles in the regulation of proliferation, cell fate, the self-renewal of stem and progenitor cells, and tumorigenesis. Long noncoding RNAs (lncRNAs), non–protein-coding transcripts longer than 200 nt, also play important roles in a number of biological processes and in tumorigenesis. We show that the lncRNA <i>ASBEL</i> [antisense ncRNA in the ANA (Abundant in neuroepithelium area)/BTG3 (B-cell translocation gene 3) locus] and transcription factor 3 (TCF3) are directly transactivated by β-catenin and form a complex that downregulates the expression of activating transcription factor 3 (ATF3). We further demonstrate that <i>ASBEL</i>–TCF3–mediated downregulation of ATF3 expression is required for the tumorigenicity of colon cancer cells. Our results suggest that the β-catenin– <i>ASBEL</i>–TCF3–ATF3 pathway may be a promising target for colon cancer therapy. </p><p class="first" id="d6499388e266">Wnt/β-catenin signaling plays a key role in the tumorigenicity of colon cancer. Furthermore, it has been reported that lncRNAs are dysregulated in several steps of cancer development. Here we show that β-catenin directly activates the transcription of the long noncoding RNA (lncRNA) <i>ASBEL</i> [antisense ncRNA in the ANA (Abundant in neuroepithelium area)/BTG3 (B-cell translocation gene 3) locus] and transcription factor 3 (TCF3), both of which are required for the survival and tumorigenicity of colorectal cancer cells. <i>ASBEL</i> interacts with and recruits TCF3 to the activating transcription factor 3 ( <i>ATF3</i>) locus, where it represses the expression of ATF3. Furthermore, we demonstrate that <i>ASBEL</i>–TCF3–mediated down-regulation of ATF3 expression is required for the proliferation and tumorigenicity of colon tumor cells. ATF3, in turn, represses the expression of <i>ASBEL</i>. Our results reveal a pathway involving an lncRNA and two transcription factors that plays a key role in Wnt/β–catenin–mediated tumorigenesis. These results may provide insights into the variety of biological and pathological processes regulated by Wnt/β-catenin signaling. </p>