Overexpression of VIRMA confers vulnerability to breast cancers via the m6A-dependent regulation of unfolded protein response

Sep 24, 2026

Uploaded by Levi

Virilizer-like m6A methyltransferase-associated protein (VIRMA) stabilizes the m6A writer complex, yet the consequences of aberrant VIRMA expression in human disease are unclear. VIRMA is amplified and overexpressed in 15–20% of breast cancers. The nuclear-enriched full-length isoform drives m6A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, VIRMA increases m6A-modified NEAT1 and enriches m6A on unfolded protein response (UPR) regulators without translating them under optimal growth, but enhances UPR and cell death susceptibility under stress typical of tumour microenvironments.

LanguageEnglish

CategoryHealthcare

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Pages20

Reading Time50 min

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Abstract

Introduction

Cellular and Molecular Life Sciences (2023) 80:157 [https://doi.org/10.1007/s00018-023-04799-4](https://doi.org/10.1007/s00018-023-04799-4) Cellular and Molecular Life Sciences Overexpression of VIRMA confers vulnerability to breast cancers via the m6A‑dependent regulation of unfolded protein response Quintin Lee1,2 · Renhua Song1,2 · Dang AnhVu Phan1,2 · Natalia Pinello1,2 · Jessica Tieng1,2 · Anni Su1,2 · James M. Halstead1,2 · Alex C. H. Wong1,2,3 · Michelle van Geldermalsen1,2 · Bob S.‑L. Lee4 · Bowen Rong5,6 · Kristina M. Cook2,7 · Mark Larance2,7 · Renjing Liu4,8 · Fei Lan5,6 · Jessamy C. Tiffen2,9 · Justin J.‑L. Wong1,2,7,10 Received: 6 February 2023 / Revised: 4 May 2023 / Accepted: 4 May 2023 / Published online: 19 May 2023 © The Author(s) 2023, Corrected published 2023 Abstract Virilizer-like m6A methyltransferase-associated protein (VIRMA) maintains the stability of the m6A writer complex. Although VIRMA is critical for RNA m6A deposition, the impact of aberrant VIRMA expression in human diseases remains unclear. We show that VIRMA is amplified and overexpressed in 15–20% of breast cancers. Of the two known VIRMA isoforms, the nuclear-enriched full-length but not the cytoplasmic-localised N-terminal VIRMA promotes m6A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the m6A-modified long non-coding RNA, NEAT1, which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches m6A on transcripts that regulate the unfolded protein response (UPR) pathway but does not promote their translation to activate the UPR under optimal growth conditions. Under stressful conditions that are often present in tumour microenvironments, VIRMA-overexpressing cells display enhanced UPR and increased susceptibility to death. Our study identifies oncogenic VIRMA overexpression as a vulnerability that may be exploited for cancer therapy. Keywords N6-methyladenosine (m6a) · Messenger RNA · VIRMA · Unfolded protein response · Endoplasmic reticulum stress · Breast cancer Quintin Lee, Renhua Song, Dang Anh Vu Phan, Natalia Pinello, Jessica Tieng: contributed equally. * Justin J.-L. Wong [j.wong@centenary.org.au](j.wong@centenary.org.au) 1 Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW 2006, Australia 2 Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia 3 Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2006, Australia 4 Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia 5 Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics Introduction Modifications to RNA molecules regulate normal cell development and are implicated in cancers. Of over 170 RNA modifications reported to date [1], methylation of N6-adenosine (m6A) residues is the most prevalent internal and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China 6 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China 7 Charles Perkins Centre, University of Sydney, Camperdown, NSW 2006, Australia 8 School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW 2052, Australia 9 Melanoma Epigenetics Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW 2006, Australia 10 Locked Bag 6, Newtown, NSW 2042, Australia modification on messenger RNAs (mRNAs) and is present on non-coding RNAs [2, 3] . m6A is deposited by a core m6A methyltransferase complex comprising Methyltransferase-3 (METTL3), Methyltransferase-14 (METTL14) and Wilm's Tumor Associated Protein (WTAP) [4] . While mutations of m6A regulators are rare (0 .02–8.07%) [5–7], aberra

FAQs

What role does VIRMA play in m6A biology?

VIRMA maintains the stability of the m6A writer complex, supporting m6A deposition on RNA. It acts to ensure proper function of core m6A methylation machinery.

How is VIRMA altered in breast cancer?

VIRMA is amplified and overexpressed in 15–20% of breast cancers, and distinct VIRMA isoforms show different effects on tumourigenesis.

Why does VIRMA overexpression increase vulnerability under stressful conditions?

Under stress conditions similar to tumour microenvironments, VIRMA-overexpressing cells display enhanced unfolded protein response (UPR) and increased susceptibility to death, making VIRMA a potential therapeutic vulnerability.

Sep 24, 2026

Uploaded by Levi