Overexpression of VIRMA confers vulnerability to breast cancers via the m 6 A-dependent regulation of unfolded protein response.

Autor: Lee Q; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Song R; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Phan DAV; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Pinello N; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Tieng J; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Su A; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Halstead JM; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Wong ACH; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.; Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia., van Geldermalsen M; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia., Lee BS; Victor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia., Rong B; 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.; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China., Cook KM; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.; Charles Perkins Centre, University of Sydney, Camperdown, NSW, 2006, Australia., Larance M; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.; Charles Perkins Centre, University of Sydney, Camperdown, NSW, 2006, Australia., Liu R; Victor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, 2052, Australia., Lan F; 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.; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China., Tiffen JC; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.; Melanoma Epigenetics Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia., Wong JJ; Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2006, Australia. j.wong@centenary.org.au.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia. j.wong@centenary.org.au.; Charles Perkins Centre, University of Sydney, Camperdown, NSW, 2006, Australia. j.wong@centenary.org.au.; Locked Bag 6, Newtown, NSW, 2042, Australia. j.wong@centenary.org.au.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2023 May 19; Vol. 80 (6), pp. 157. Date of Electronic Publication: 2023 May 19.
DOI: 10.1007/s00018-023-04799-4
Abstrakt: Virilizer-like m 6 A methyltransferase-associated protein (VIRMA) maintains the stability of the m 6 A writer complex. Although VIRMA is critical for RNA m 6 A 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 m 6 A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the m 6 A-modified long non-coding RNA, NEAT1, which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches m 6 A 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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