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

Sangkyeong Eom, Jongjin Peak, Jongyeun Park, Seung Hyun Ahn, You Kyung Cho, Yeahji Jeong, Hye Sook Lee, Jung Lee, Elizaveta Ignatova, Sung Eun Lee, Yunji Hong, Dowoon Gu, Geun Woo D. Kim, Dong Chan Lee, Ja Young Hahm, Jaemin Jeong, Dongho Choi, Eun Sook Jang, Sung Wook Chi

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1369-1383
Number of pages15
JournalNature Cell Biology
Volume25
Issue number9
DOIs
Publication statusPublished - 2023 Sept

Bibliographical note

Funding Information:
We thank all members of the Chi laboratory for their help and discussions. We are especially grateful to the late S.-D. Yoo and the Y.S. Lee for motivating us to strive to understand liver cancer. We thank J.-W. Nam for his help in initiating the TCGA data analysis, S.-H. Koo for providing the albumin promoter-containing vector, M.-S. Lee for providing SK-HEP-1, J. Hwang for help with arranging clinical samples, J. H. Kim for his help in preliminary studies on glioblastoma, Y. Koh for help in analysing RNA-seq data, and Y. Jeong, D.-N. Lee, Y. Kang and K.-H. Lee for their initial assistance in preliminary studies. This work was supported by the Samsung Research Funding & Incubation Center of Samsung Electronics under project number SRFC-MA1801-10, grants from the NRF funded by the Ministry of Science, ICT & Future Planning (NRF-2023R1A2C3005802, to S.W.C.; NRF-2021R1I1A1A01045508, to S.E.), Korea University grants, the KU-KIST Graduate School of Converging Science and Technology Program, and Korea Institute of Science and Technology (KIST) Institutional Program (2V09840). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

  • Cell Biology

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