MYC Superenhancer–Nuclear Pore Binding Increases MYC-Transcript Export

Gene gating, a phenomenon in which inducible genes are kept in proximity to nuclear pores to facilitate the genes’ repeated activation and increase the rate of export of their transcripts from the nucleus, has been documented in yeast and lower animals. Scholz, Sumida, and colleagues discovered that this principle affects MYC, a gene that promotes cancer development when aberrantly activated in human cancer cells. Specifically, MYC and an associated oncogenic superenhancer (OSE) were shown to associate with protein constituents of the nuclear-pore complex called nucleoporins in human colon-cancer cells, but not in normal colon epithelial cells. Correspondingly, the rate of nuclear transport of MYC transcripts was elevated in colon-cancer cells relative to normal cells. The rate of transcript degradation in the nucleus is substantially greater than the rate in the cytoplasm; thus, the increased export of MYC transcripts resulted in an elevated level of cytoplasmic MYC mRNA in the colon-cancer cells. Mechanistically, tethering of the MYC-associated OSE to the nuclear pore and the associated increase in the rate of nuclear export of MYC transcripts required AHCTF1 (also known as ELYS), a transcription factor previously found to be responsible for recruiting a subcomplex of the nuclear pore to chromatin. β-catenin mediated the interaction between AHCTF1 and the OSE, and treatment with a β-catenin inhibitor reduced export of MYC transcripts to the cytoplasm, linking canonical WNT signaling to MYC gating. Together, these results provide multiple lines of evidence supporting WNT signaling–mediated, cancer cell–specific gating of the established proto-oncogene MYC, providing new avenues to explore for cancer pathogenesis and possibly treatment.

Scholz BA, Sumida N, de Lima CDM, Chachoua I, Martino M, Tzelepis I, et al. WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating. Nat Genet 2019;51:1723–31.

• ©2019 American Association for Cancer Research.