Abstract
CFIm25 acts as a tumor suppressor by repressing use of 3′ UTR proximal polyadenylation sites.
Major finding: CFIm25 acts as a tumor suppressor by repressing use of 3′ UTR proximal polyadenylation sites.
Concept: Derepression of alternative polyadenylation can lead to removal of negative regulatory elements.
Impact: Deregulation of RNA 3′end processing can induce broad gene expression changes that promote tumor growth.
Alternative polyadenylation leads to mRNA shortening via utilization of polyadenylation sites nearest to stop codons and occurs in rapidly proliferating and transformed cells, but the contributions of alternative polyadenylation and RNA 3′-end-processing factors to tumorigenesis remain poorly understood. Masamha and colleagues observed that proximal polyadenylation site usage in transcripts known to undergo alternative polyadenylation was repressed in HeLa cells despite their highly transformed phenotype. An RNA interference screen for genes involved in repression of alternative polyadenylation identified a requirement for members of the cleavage factor Im (CFIm) complex, particularly CFIm25. Bioinformatic analysis of RNA sequencing reads showed that CFIm25 knockdown caused shifts to proximal polyadenylation sites in the 3′ untranslated region (UTR) of 1,450 transcripts. Shortening of the 3′ UTR resulted in increased expression of a high proportion of affected transcripts, with gene expression positively correlating with the removal of 3′ UTR negative regulatory elements such as miRNA target sites and AU-rich elements. Of note, CFIm25 target genes included several oncogenes, raising the possibility that CFIm25 expression levels may affect cell growth. Indeed, CFIm25-depleted HeLa cells showed enhanced proliferation. To test the hypothesis that CFIm25 loss promotes oncogenic alternative polyadenylation in primary tumors, the authors evaluated glioblastoma samples, given that 3′ UTRs in the brain are particularly long. Analysis of glioblastoma samples from The Cancer Genome Atlas identified 59 genes that underwent 3′ UTR shortening in tumors with low CFIm25 expression. Expression of CFIm25 in a glioblastoma cell line with low endogenous levels of CFIm25 impaired anchorage-independent growth and invasive behavior in vitro and reduced growth in a xenograft transplant model, whereas CFIm25 knockdown in a glioblastoma cell line with high endogenous CFIm25 expression increased tumor growth. Together, these data suggest that CFIm25 acts as a tumor suppressor and that alternative polyadenylation may play a role in oncogenesis.
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