VIRMA contributes to non-small cell lung cancer progression via N6-methyladenosine-dependent DAPK3 post-transcriptional modification

Xu, Yongfang; Chen, Yunhao; Yao, Yinan; Xie, Haiyang; Lü, Guohua; Du, Chengli; Cheng, Jun; Zhou, Jianying

doi:10.1016/j.canlet.2021.08.027

Cited by 36 publications

(34 citation statements)

References 28 publications

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“…Within LUSC subtype, METTL3, VIRMA and HNRNPC genes were significantly correlated with the prognosis of patients. This is consistent with the current research results [34][35][36]. However, the regression analysis yield no statistically significant results in LUSC.…”

Section: Discussionsupporting

confidence: 92%

M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer

Liu

et al. 2022

Preprint

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Background: The m6A methylation modification is one of the most common mRNA modifications, and involved in a variety of biological processes, such as cell death, cancer stem cell formation and tumorigenesis. Increasing evidences have demonstrated that the expression patterns of m6A regulators are significantly correlated with PD-L1 level some solid tumors, but few study has explored the function of m6A regulators in the immune microenvironment and prognosis in non-small cell lung cancer (NSCLC). Methods: Survival analysis was independently conducted for 20 m6A regulators to explore their prognostic value in NSCLC, and then the prognostic risk model based on m6A regulator expression profiles is built to stratify NSCLC patients. Also, the correlation analysis between immune infiltrating cells and m6A regulators is used to reveal the impact of m6A on immune microenvironment of NSCLC. Furthermore, to explore the function of m6A as biomarker of anit-PD-L1 therapeutic effect, we explored the associations of tumor mutation burden (TMB) and PD-L1 levels to 20 m6A regulator expression patterns in NSCLC. Results: First, the expressions of 20 m6A regulators in NSCLC tissues were significantly increased compared to normal tissues. Survival analysis revealed that three genes, METTL3, HNRNPC and VIRMA, were markedly correlated to the prognosis of NSCLC patients. In particular, cox regression analysis verified that METTL3 could be used as an independent prognostic factor to predict the survival rate of NSCLC patients. Second, the risk prognostic model built on seven m6A regulators can effectively stratify NSCLC patients, and the low-risk subgroup had better prognosis compared to high-risk group. Finally, a few m6A regulators showed significant associations with immune microenvironment, as well as TMB and PD-L1 level, suggesting that the m6A RNA methylation is indicative of therapeutic effect of anti-PD-L1 treatment. Conclusion: Our study identified some m6A regulatory factors as independent risk factors for the prognosis of NSCLC, and the expression patterns of m6A regulators are also correlated to the immune infiltration, as well as TMB and PD-L1 level in NSCLC. The m6A regulators could be used as biomarkers indicative of immunotherapy to NSCLC patients.

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Section: Discussionsupporting

confidence: 92%

M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer

Liu

et al. 2022

Preprint

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“…Furthermore, three additional networks were automatically identified by IPA among the Top 50 non-mutated genes (Additional file 1 : Figure S1a). We show one network consisting of 12 genes including ANKLE2, SHROOM3 and ELFN2 interacting through direct connections with VIRMA, a nuclear/cytosolic protein involved in RNA methylation/adenylation and implicated in different cancers [ 97 , 98 ]. These results show that the identified non-mutated genes interact in cancer related biological pathways.…”

Section: Resultsmentioning

confidence: 99%

Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes

et al. 2022

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Background Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. Methods We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. Results We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. Conclusion We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.

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Section: The Role Of M 6 a In Diverse Cellular Fun...mentioning

confidence: 99%

“…Additionally, VIRMA was found to promote non-small cell lung cancer (NSCLC) and increased NSCLC proliferation in vitro and in vivo ( Xu et al, 2021 ). Mechanistically, VIRMA promoted the mRNA decay of tumor suppressor Dapk3 through an m 6 A-dependent YTHDF2/YTHDF3-mediated mechanism ( Xu et al, 2021 ). Furthermore, VIRMA was found to promote breast cancer progression by promoting the mRNA stability of Cdk1 in an m 6 A-independent manner ( Qian et al, 2019 ).…”

Section: The Role Of M 6 a In Diverse Cellular Fun...mentioning

confidence: 99%

Roles of RNA Modifications in Diverse Cellular Functions

Wilkinson

Cui

2022

Front. Cell Dev. Biol.

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Chemical modifications of RNA molecules regulate both RNA metabolism and fate. The deposition and function of these modifications are mediated by the actions of writer, reader, and eraser proteins. At the cellular level, RNA modifications regulate several cellular processes including cell death, proliferation, senescence, differentiation, migration, metabolism, autophagy, the DNA damage response, and liquid-liquid phase separation. Emerging evidence demonstrates that RNA modifications play active roles in the physiology and etiology of multiple diseases due to their pervasive roles in cellular functions. Here, we will summarize recent advances in the regulatory and functional role of RNA modifications in these cellular functions, emphasizing the context-specific roles of RNA modifications in mammalian systems. As m6A is the best studied RNA modification in biological processes, this review will summarize the emerging advances on the diverse roles of m6A in cellular functions. In addition, we will also provide an overview for the cellular functions of other RNA modifications, including m5C and m1A. Furthermore, we will also discuss the roles of RNA modifications within the context of disease etiologies and highlight recent advances in the development of therapeutics that target RNA modifications. Elucidating these context-specific functions will increase our understanding of how these modifications become dysregulated during disease pathogenesis and may provide new opportunities for improving disease prevention and therapy by targeting these pathways.

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VIRMA contributes to non-small cell lung cancer progression via N6-methyladenosine-dependent DAPK3 post-transcriptional modification

Cited by 36 publications

References 28 publications

M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer

M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer

Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes

Roles of RNA Modifications in Diverse Cellular Functions

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