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.
Cell Mol Life Sci. 2023 May 19;80(6):157. doi: 10.1007/s00018-023-04799-4.
Virilizer-like mA methyltransferase-associated protein (VIRMA) maintains the stability of the mA writer complex. Although VIRMA is critical for RNA mA 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 mA-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the mA-modified long non-coding RNA, NEAT1, which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches mA 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.
VIRMA 样 mA 甲基转移酶相关蛋白 (VIRMA) 维持 mA 书写复合物的稳定性。尽管 VIRMA 对 RNA mA 沉积至关重要，但异常 VIRMA 表达在人类疾病中的影响尚不清楚。我们表明，VIRMA 在 15-20%的乳腺癌中扩增和过表达。在两种已知的 VIRMA 异构体中，富含核的全长而非细胞质定位的 N 端 VIRMA 促进体外和体内 mA 依赖性乳腺癌发生。在机制上，我们揭示了 VIRMA 过表达上调 mA 修饰的长非编码 RNA NEAT1，这有助于乳腺癌细胞生长。我们还表明，VIRMA 过表达会使调节未折叠蛋白反应 (UPR) 途径的转录本上的 mA 富集，但在最佳生长条件下不会促进其翻译以激活 UPR。在肿瘤微环境中经常存在的应激条件下，过表达 VIRMA 的细胞显示出增强的 UPR 和对死亡的敏感性增加。我们的研究确定致癌 VIRMA 过表达是一种脆弱性，可能被用于癌症治疗。
