Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3′ UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations. As APC has been previously identified as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.

中文翻译：

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APC 突变在癌症中失调替代多聚腺苷酸化


选择性多聚腺苷酸化 （APA） 影响大多数人类基因，并且在所有研究的癌症中反复失调。然而，这种失调的机制起源尚不完全清楚。我们描述了对癌症基因组图谱中 poly（A） 位点选择的分子调节因子的无偏倚分析，并确定结直肠腺癌相对于所有其他癌症亚型是一个异常值。这种区别源于结直肠腺癌中经常存在功能丧失的 APC 突变，相对于缺乏 APC 突变的肿瘤，这与长 3′ UTR 表达密切相关。APC 敲除同样会使人结肠类器官中的 APA 失调。通过挖掘先前发表的 APC eCLIP 数据，我们表明 APC 优先结合近端 poly （A） 位点上游的富含 G 和 C 的基序。最后，我们发现 APC 表达降低与缺乏复发性 APC 突变的肿瘤类型的 APA 失调有关。由于 APC 先前已被确定为一种 RNA 结合蛋白，在小鼠神经发生过程中优先结合 3' UTR，我们的结果表明 APC 促进近端 poly （A） 位点的使用，并且 APC 丢失和表达改变导致癌症中普遍的 APA 失调。