Abstract
Alternative cleavage and polyadenylation (APA) can occur at more than half of all human genes, greatly enhancing the cellular repertoire of mRNA isoforms. As these isoforms can have altered stability, localisation and coding potential, deregulation of APA can disrupt gene expression and this has been linked to many diseases including cancer progression. How APA generates cancer-specific isoform profiles and what their physiological consequences are, however, is largely unclear. Here we use a subcellular fractionation approach to determine the nuclear and cytoplasmic APA profiles of successive stages of colon cancer using a cell line-based model. Using this approach, we show that during cancer progression specific APA profiles are established. We identify that overexpression of hnRNPC has a critical role in the establishment of APA profiles characteristic for metastatic colon cancer cells, by regulating poly(A) site selection in a subset of genes that have been implicated in cancer progression including MTHFD1L.
Highlights
Cleavage and polyadenylation (CPA) is a fundamental premRNA processing reaction that matures the 3 end of almost all protein-coding genes
We show that an increase in hnRNPC in metastatic derived colon epithelial cells contributes to the upregulation of full-length MTHFD1L mRNA production by controlling poly(A) site choice
The SW480 cell line was established from a Dukes’ type B primary adenocarcinoma of the colon and the SW620 cell line was derived from a lymph node after cancer recurred with widespread metastasis [16]
Summary
Cleavage and polyadenylation (CPA) is a fundamental premRNA processing reaction that matures the 3 end of almost all protein-coding genes. Some of the most prominent APA profile changes are observed between normal and cancer cells with a tendency to express mRNA APA isoforms with shorter UTRs in the latter [7,8,9,10,11]. This shortening, in some cases, may boost the translational output of key genes such as cell cycle regulators by avoiding exposure to repressive modules such as miRNAs [11]. Despite considerable efforts and analyses of numerous APA profiles from cancer cells, how these characteristic profiles
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