WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating
WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating
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DOI：
10.1038/s41588-019-0535-3
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发表时间：
2019-12-01
期刊：
影响因子：
30.8
通讯作者：
Ohlsson, Rolf
中科院分区：
文献类型：
--
作者：
Scholz, Barbara A.;Sumida, Noriyuki;Ohlsson, Rolf
WNT信号传导激活癌细胞中的MYC表达。在这里，我们报告说，这涉及到一个致癌的超级增强子介导的拴系活性MYC等位基因的核孔，以增加转录输出率。由于MYC转录物的衰变在细胞核中比在细胞质中更快，因此致癌超级增强子促进的核MYC转录物的输出加速了它们从结肠癌细胞中的核降解系统中逃逸。如计算机建模所支持的，该过程的净总和是结肠癌细胞中比野生型细胞中更高的胞质MYC信使RNA水平。MYC的癌细胞特异性门控由AHCTF 1（也称为ELYS）调节，AHCTF 1通过β-连环蛋白将核孔蛋白连接到致癌超级增强子。我们的结论是，WNT信号与染色质结构合作，转录后失调的典型癌症驱动程序的表达。
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 beta-catenin. We conclude that WNT signaling collaborates with chromatin architecture to post-transcriptionally dysregulate the expression of a canonical cancer driver.