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

doi:10.1038/s41556-023-01209-6

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 journal › Article › peer-review

8 Citations (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 language	English
Pages (from-to)	1369-1383
Number of pages	15
Journal	Nature Cell Biology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/s41556-023-01209-6
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41556-023-01209-6

Cite this

Eom, S., Peak, J., Park, J., Ahn, S. H., Cho, Y. K., Jeong, Y., Lee, H. S., Lee, J., Ignatova, E., Lee, S. E., Hong, Y., Gu, D., Kim, G. W. D., Lee, D. C., Hahm, J. Y., Jeong, J., Choi, D., Jang, E. S., & Chi, S. W. (2023). Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development. Nature Cell Biology, 25(9), 1369-1383. https://doi.org/10.1038/s41556-023-01209-6

Eom, S, Peak, J, Park, J, Ahn, SH, Cho, YK, Jeong, Y, Lee, HS, Lee, J, Ignatova, E, Lee, SE, Hong, Y, Gu, D, Kim, GWD, Lee, DC, Hahm, JY, Jeong, J, Choi, D, Jang, ES & Chi, SW 2023, 'Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development', Nature Cell Biology, vol. 25, no. 9, pp. 1369-1383. https://doi.org/10.1038/s41556-023-01209-6

@article{23a4ab441e6c40588f10d87b28c16d4e,

title = "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.",

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

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: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = sep,

doi = "10.1038/s41556-023-01209-6",

language = "English",

volume = "25",

pages = "1369--1383",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development

AU - Eom, Sangkyeong

AU - Peak, Jongjin

AU - Park, Jongyeun

AU - Ahn, Seung Hyun

AU - Cho, You Kyung

AU - Jeong, Yeahji

AU - Lee, Hye Sook

AU - Lee, Jung

AU - Ignatova, Elizaveta

AU - Lee, Sung Eun

AU - Hong, Yunji

AU - Gu, Dowoon

AU - Kim, Geun Woo D.

AU - Lee, Dong Chan

AU - Hahm, Ja Young

AU - Jeong, Jaemin

AU - Choi, Dongho

AU - Jang, Eun Sook

AU - Chi, Sung Wook

N1 - 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.

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85170624969&partnerID=8YFLogxK

U2 - 10.1038/s41556-023-01209-6

DO - 10.1038/s41556-023-01209-6

M3 - Article

C2 - 37696949

AN - SCOPUS:85170624969

SN - 1465-7392

VL - 25

SP - 1369

EP - 1383

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 9

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this