The HIF and mTOR pathways orchestrate responses to oxygen and nutrient availability. They are frequently dysregulated in cancer and are both prime targets for therapy. Yet their interplay in cancer cells is poorly understood due to technical difficulties of simultaneously measuring both global translation of gene transcripts, or mRNAs, into proteins and the translation of specific mRNAs. Ludwig Oxford’s Peter Ratcliffe and his colleagues reported in a September study in Nature Structural & Molecular Biology a new approach to measuring both at the same time and the application of their method to analyzing the interplay of transcriptional and translational regulation by the two signaling pathways in the most common type of kidney cancer, clear cell renal carcinoma. The findings show that mTOR dysregulation broadly alters protein translation, exerting an effect on many metabolic pathways. HIF pathway dysregulation, on the other hand, has an effect on a more limited set of genes. Their analysis shows that specific classes of HIF1A and HIF2A transcriptional target genes manifest different sensitivity to mTOR and do so in a manner that supports combined use of HIF2A and mTOR inhibitors in the treatment of this type of kidney cancer.
Isoform-resolved mRNA profiling of ribosome load defines interplay of HIF and mTOR dysregulation in kidney cancer
Nature Structural & Molecular Biology, 2022 September 12