Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development

Abstract

Oxidative stress contributes to tumourigenesis by altering gene expression. One accompanying modification, 8-oxoguanine (o⁸G) can change RNA-RNA interactions via o⁸G•A base pairing, but its regulatory roles remain elusive. Here, on the basis of o⁸G-induced guanine-to-thymine (o⁸G > T) variations featured in sequencing, we discovered widespread position-specific o⁸Gs in tumour microRNAs, preferentially oxidized towards 5' end seed regions (positions 2-8) with clustered sequence patterns and clinically associated with patients in lower-grade gliomas and liver hepatocellular carcinoma. We validated that o⁸G at position 4 of miR-124 (4o⁸G-miR-124) and 4o⁸G-let-7 suppress lower-grade gliomas, whereas 3o⁸G-miR-122 and 4o⁸G-let-7 promote malignancy of liver hepatocellular carcinoma by redirecting the target transcriptome to oncogenic regulatory pathways. Stepwise oxidation from tumour-promoting 3o⁸G-miR-122 to tumour-suppressing 2,3o⁸G-miR-122 occurs and its specific modulation in mouse liver effectively attenuates diethylnitrosamine-induced hepatocarcinogenesis. These findings provide resources and insights into epitranscriptional o⁸G regulation of microRNA functions, reprogrammed by redox changes, implicating its control for cancer treatment.