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

Quintin Lee; Renhua Song; Dang Anh Vu Phan; Natalia Pinello; Jessica Tieng; Anni Su; James M Halstead; Alex C H Wong; Michelle van Geldermalsen; Bob S-L Lee; Bowen Rong; Kristina M Cook; Mark Larance; Renjing Liu; Fei Lan; Jessamy C Tiffen; Justin J-L Wong

doi:10.1007/s00018-023-04799-4

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

Cell Mol Life Sci. 2023 May 19;80(6):157. doi: 10.1007/s00018-023-04799-4.

Authors

Quintin Lee^#^{1

2}, Renhua Song^#^{1

2}, Dang Anh Vu Phan^#^{1

2}, Natalia Pinello^#^{1

2}, Jessica Tieng^#^{1

2}, Anni Su^{1

2}, James M Halstead^{1

2}, Alex C H Wong^{1

2

3}, Michelle van Geldermalsen^{1

2}, Bob S-L Lee⁴, Bowen Rong^{5

6}, Kristina M Cook^{2

7}, Mark Larance^{2

7}, Renjing Liu^{4

8}, Fei Lan^{5

6}, Jessamy C Tiffen^{2

9}, Justin J-L Wong^{10

11

12

13}

Affiliations

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 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 Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia. j.wong@centenary.org.au.
¹¹ Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia. j.wong@centenary.org.au.
¹² Charles Perkins Centre, University of Sydney, Camperdown, NSW, 2006, Australia. j.wong@centenary.org.au.
¹³ , Locked Bag 6, Newtown, NSW, 2042, Australia. j.wong@centenary.org.au.

^# Contributed equally.

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: Breast cancer; Endoplasmic reticulum stress; Messenger RNA; N6-methyladenosine (m6a); Unfolded protein response; VIRMA.

MeSH terms

Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Female
Humans
RNA / metabolism
RNA Interference
Tumor Microenvironment
Unfolded Protein Response / genetics

Substances

RNA

Grants and funding

RG21-07/Cancer Council NSW