Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 45, Pages 12739-12744Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1605938113
Keywords
beta-catenin; noncoding RNA; ASBEL; colorectal tumorigenesis; ATF3
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Funding
- Innovative Technology Research Program of Innovative Cell Biology (Integrated Systems Analysis of Cellular Oncogenic Signaling Networks)
- Project for the Development of Innovative Research on Cancer Therapeutics, Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [15H01464, 15K08299, 15H02369] Funding Source: KAKEN
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Wnt/beta-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 beta-catenin directly activates the transcription of the long noncoding RNA (lncRNA) ASBEL [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. ASBEL interacts with and recruits TCF3 to the activating transcription factor 3 (ATF3) locus, where it represses the expression of ATF3. Furthermore, we demonstrate that ASBEL-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 ASBEL. Our results reveal a pathway involving an lncRNA and two transcription factors that plays a key role in Wnt/beta-catenin-mediated tumorigenesis. These results may provide insights into the variety of biological and pathological processes regulated by Wnt/beta-catenin signaling.
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