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

• Published in: Cell reports (Cambridge) Vol. 40; no. 3; p. 111104
• Main Authors: Reggiardo, Roman E., Maroli, Sreelakshmi Velandi, Halasz, Haley, Ozen, Mehmet, Hrabeta-Robinson, Eva, Behera, Amit, Peddu, Vikas, Carrillo, David, LaMontagne, Erin, Whitehead, Lila, Kim, Eejung, Malik, Shivani, Fernandes, Jason, Marinov, Georgi, Collisson, Eric, Brooks, Angela, Demirci, Utkan, Kim, Daniel H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 19.07.2022
• Subjects: cancer; extracellular RNA; extracellular vesicles; interferon-stimulated genes; KRAS; KZNF; noncoding RNA; RAS signaling; RNA biomarker; transposable element; RNA biomarker; noncoding RNA; extracellular vesicles; KZNF; transposable element; extracellular RNA; CP: Molecular biology; KRAS; cancer; interferon-stimulated genes; RAS signaling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111104

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 find 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 an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway. [Display omitted] •Mutant KRAS signaling activates an intrinsic interferon-stimulated gene signature•KRAB zinc-finger genes are silenced in mutant KRAS cells in vitro and in vivo•Transposable element (TE) noncoding RNAs are upregulated by mutant KRAS signaling•Mutant KRAS cells preferentially secrete TE noncoding RNA in extracellular vesicles Many human cancers are driven by mutant KRAS, but its effects on noncoding RNA are unclear. Reggiardo et al. show that mutant KRAS regulates this RNA landscape by silencing KRAB zinc-finger genes that normally repress transposable element noncoding RNAs, which are preferentially released from mutant KRAS cells in extracellular vesicles.