The online version of this article (https://doi.org/10.1186/s12943-017-0749-x) contains supplementary material, which is available to authorized users.
FHIT 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.
Ribosome 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.
In 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.
Additional file 1: Detailed presentation of methods used for ribosome profiling and bioinformatics analysis. (PDF 84 kb)
Additional file 3: Scatterplots of duplicate RNA-Seq libraries from Fhit-deficient (E1) and Fhit-expressing (D1) H1299 cells. (PDF 688 kb)
Additional file 4: Excel file listing all of the transcripts identified by RNA-Seq as having increased or decreased steady-state as a function of Fhit expression. These are ordered by fold change and statistical significance. (XLSX 110 kb)
Additional file 5: Scatterplots of duplicate ribosome profiling libraries from Fhit-deficient (E1) and Fhit-expressing (D1) H1299 cells. (PDF 639 kb)
Additional file 6: Metagene analysis showing the 3 nucleotide periodicity of bound ribosomes. (PDF 333 kb)
Additional file 7: Excel file listing all of the transcripts identified by RIBO-Seq as having increased or decreased ribosome occupancy as a function of Fhit expression. These are ordered by fold change and statistical significance. (XLSX 25 kb)
Additional file 8: Scatterplots of average ribosome density of duplicate Fhit- negative (E1) and Fhit-expressing (D1) H1299 cells. (PDF 770 kb)
Additional file 9: Upstream open reading frames within the 5’-UTRs of Fhit-regulated mRNAs. (XLSX 27 kb)
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- Impact of FHIT loss on the translation of cancer-associated mRNAs
Daniel L. Kiss
Daniel R. Schoenberg
- BioMed Central
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