WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating

• Published in: Nature genetics Vol. 51; no. 12; pp. 1723 - 1731
• Main Authors: Scholz, Barbara A., Sumida, Noriyuki, de Lima, Carolina Diettrich Mallet, Chachoua, Ilyas, Martino, Mirco, Tzelepis, Ilias, Nikoshkov, Andrej, Zhao, Honglei, Mehmood, Rashid, Sifakis, Emmanouil G., Bhartiya, Deeksha, Göndör, Anita, Ohlsson, Rolf
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2019; Nature Publishing Group
• Subjects: 13/1; 13/95; 14/19; 38/32; 38/47; 45/77; 45/90; 631/208; 631/337; 631/67; 631/80; 692/699; 82/51; 96/63; 96/95; Agriculture; Analysis; Animal Genetics and Genomics; beta Catenin - genetics; beta Catenin - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell cycle; Chromatin; Colon; Colon - cytology; Colon cancer; Colorectal cancer; Cytoplasm; Deoxyribonucleic acid; DNA; DNA methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Epigenetics; Epithelial Cells - physiology; Exports; Gating; Gene expression; Gene Expression Regulation, Neoplastic; Gene Function; Genes, myc; Genomes; HCT116 Cells; Human Genetics; Humans; International economic relations; Mammals; Medicin och hälsovetenskap; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - metabolism; mRNA; Myc protein; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Nuclear pores; Nucleoporins; Post-transcription; Protein Transport; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA; RNA Processing, Post-Transcriptional; Scientific equipment and supplies industry; Signaling; Stem cells; Tethering; Transcription Factors - genetics; Transcription Factors - metabolism; Wnt protein; Wnt Signaling Pathway - genetics; β-Catenin; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-019-0535-3

WNT signaling activates MYC expression in cancer cells. Here we report that this involves an oncogenic super-enhancer-mediated tethering of active MYC alleles to nuclear pores to increase transcript export rates. As the decay of MYC transcripts is more rapid in the nucleus than in the cytoplasm, the oncogenic super-enhancer-facilitated export of nuclear MYC transcripts expedites their escape from the nuclear degradation system in colon cancer cells. The net sum of this process, as supported by computer modeling, is greater cytoplasmic MYC messenger RNA levels in colon cancer cells than in wild type cells. The cancer-cell-specific gating of MYC is regulated by AHCTF1 (also known as ELYS), which connects nucleoporins to the oncogenic super-enhancer via β-catenin. We conclude that WNT signaling collaborates with chromatin architecture to post-transcriptionally dysregulate the expression of a canonical cancer driver. Oncogenic MYC expression involves super-enhancer-mediated tethering of MYC alleles to nuclear pores, thus increasing messenger RNA export. This is regulated by AHCTF1 and β-catenin.