Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes

RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regu-lated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit dif-ferential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive non-coding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.

Automated summary

The study found that oncogenic KRAS signaling upregulates noncoding transcripts, many of which come from transposable elements, while also regulating the expression of KRAB zinc finger genes and IFN-stimulated genes. These results reveal that mutant KRAS remodels the repetitive non-coding transcriptome, regulating a broad range of intracellular and extracellular RNAs.