CFIm25 links alternative polyadenylation to glioblastoma tumour suppression

被引:328
|
作者
Masamha, Chioniso P. [1 ]
Xia, Zheng [2 ,3 ]
Yang, Jingxuan [4 ]
Albrecht, Todd R. [1 ]
Li, Min [4 ]
Shyu, Ann-Bin [1 ]
Li, Wei [2 ,3 ]
Wagner, Eric J. [1 ]
机构
[1] Univ Texas Houston, Sch Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[4] Univ Texas Houston, Sch Med, Vivian L Smith Dept Neurosurg, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
3' UNTRANSLATED REGIONS; MESSENGER-RNAS; GLUTAMINE-METABOLISM; PROSTATE-CANCER; ANTISENSE RNA; C-MYC; GROWTH; WIDESPREAD; EXPRESSION; MICRORNAS;
D O I
10.1038/nature13261
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(1,2). 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(3); 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 CFIm25knockdown, 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 39 UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, where as 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.
引用
收藏
页码:412 / +
页数:16
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