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-regulated noncoding RNAs. We found that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential 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 the epigenetic reprogramming of IFN-stimulated genes (ISGs), some of which are also regulated by KZNFs. Our results reveal that mutant KRAS remodels the noncoding transcriptome via KZNF-mediated epigenomic reprogramming, revealing the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway. Overall design: Comparative gene expression analysis of cell lines (6x AALE and 6x HBEC) expressing mutant KRAS (3x G12D and 3x G12V, resp) and extracellular vesicles secreted from AALE (6x).