title: CFIm25 links alternative polyadenylation to glioblastoma tumour suppression.
abstract: The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3' untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA 3'-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-sequencing data for novel APA events, we identified at least 1,450 genes with shortened 3' UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNAs in human cells. Marked increases in the expression of several known oncogenes, including cyclin D1, are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3' UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, whereas CFIm25 overexpression reduces these properties and inhibits tumour growth. These findings identify a pivotal role of CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA [2].
authors.forename: Chioniso P
authors.initials: CP
authors.lastname: Masamha
authors.affiliation: 1] Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030 Texas, USA [2].
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Albrecht
authors.affiliation: The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Ann-Bin
authors.initials: AB
authors.lastname: Shyu
authors.affiliation: Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030 Texas, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Wagner
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000503:physiopathology*; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D026723:Polyadenylation; D012333:RNA, Messenger / Q000378:metabolism*; D012044:Regression Analysis; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D039221:mRNA Cleavage and Polyadenylation Factors