Impact of FHIT loss on the translation of cancer-associated mRNAs

Molecular Cancer

Research

Daniel R. Schoenberg¹  Daniel L. Kiss²  Ralf Bundschuh³  Kay Huebner⁴  William Baez⁵ 

[1] Center for RNA Biology, The Ohio State University, 43210, Columbus, OH, USA;Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, OH, USA;Department of Biological Chemistry and Pharmacology, The Ohio State University, 43210, Columbus, OH, USA;Center for RNA Biology, The Ohio State University, 43210, Columbus, OH, USA;Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, OH, USA;Department of Biological Chemistry and Pharmacology, The Ohio State University, 43210, Columbus, OH, USA;Biomarker Research Program, Houston Methodist Research Institute, TX 77030, Houston, USA;Center for RNA Biology, The Ohio State University, 43210, Columbus, OH, USA;Department of Physics, The Ohio State University, 43210, Columbus, OH, USA;Department of Chemistry & Biochemistry, The Ohio State University, 43210, Columbus, OH, USA;Division of Hematology, Department of Internal Medicine, The Ohio State University, 43210, Columbus, OH, USA;Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, OH, USA;Department of Cancer Biology and Genetics, The Ohio State University, 43210, Columbus, OH, USA;Department of Physics, The Ohio State University, 43210, Columbus, OH, USA;

关键词: Fhit;    Translational control;    Ribosome profiling;    Scavenger decapping;    Gene expression;   

DOI  :  10.1186/s12943-017-0749-x

 received in 2017-10-09, accepted in 2017-12-10,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundFHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5′,5′-triphosphates, including the m7GpppN ‘caps’ that are generated when mRNAs undergo 3′-5′ decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules. ResultsRibosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5’-UTR ribosome occupancy and this analysis also identified ribosome binding to 5′-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5’-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy. ConclusionsIn summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit’s genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy.

【 授权许可】

CC BY   
© The Author(s). 2017