A pan-cancer analysis reveals genetic alterations, molecular mechanisms, and clinical relevance of m5 C regulators.
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ABSTRACT:
SUBMITTER: Du E
PROVIDER: S-EPMC7507430 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
A pan-cancer analysis reveals genetic alterations, molecular mechanisms, and clinical relevance of m<sup>5</sup> C regulators.
Du E E Li Jingxian J Sheng Fei F Li Shuai S Zhu Jianqiang J Xu Yong Y Zhang Zhihong Z
Clinical and translational medicine 20200901 5
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Project description:Prostate cancer is a leading malignancy in the male population globally. N6-methylation of adenosine (m6A) is the most prevalent mRNA modification and plays an essential role in various biological processes in vivo. However, the potential roles of m6A in metastatic prostate cancer are largely unknown. In this study, we evaluated and identified two m6A modification patterns based on 21 m6A regulators in four public metastatic prostate cancer datasets. Different modification patterns correlated with distinct molecular characteristics. According to m6A-associated genes, we constructed a prognostic model, called m6Ascore, to predict the outcomes of patients with metastatic prostate cancer. We found that high m6A score level was related to dismal prognosis and characterized by higher cell cycle, DNA repair and mismatch repair pathway score. In vitro experiments confirmed that upregulation of METTL14, an m6A writer, enhanced the invasion, metastasis, and sensitivity of prostate cancer cells to poly (ADP-ribose) polymerase inhibitor. Conversely, down-regulation of potential target genes of m6A had the opposite effect. Finally, we validated that a higher m6A score was associated with a worse prognosis and a higher Gleason score in The Cancer Genome Atlas Program (TCGA) cohort. This work illustrated the nonnegligible role of m6A modification in multiple biological processes of metastatic prostate cancer. Evaluating the m6A risk scores of individual tumours will guide more effective judgement of prognosis as well as treatments for metastatic prostate cancer in clinical practice.
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Project description:BackgroundLysine acetylation and deacetylation are posttranslational modifications that are able to link extracellular signals to intracellular responses. However, knowledge regarding the status of lysine regulators in urological cancers is still unknown.MethodsWe first systematically analyzed the genetic and expression alterations of 31 lysine acetylation regulators in urological cancers. The correlation between lysine acetylation regulators and activation of cancer pathways was explored. The clinical relevance of lysine acetylation regulators was further analyzed.ResultsWe identified that there are widespread genetic alterations of lysine acetylation regulators, and that their expression levels are significantly associated with the activity of cancer hallmark-related pathways. Moreover, lysine acetylation regulators were found to be potentially useful for prognostic stratification. HDAC11 may act as a potential oncogene in cell cycle and oxidative phosphorylation of urological cancers.ConclusionLysine acetylation regulators are involved in tumorigenesis and progression. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of lysine acetylation regulators in urological cancers.
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Project description:Ion channels, transporters, and other ion-flux controlling proteins, collectively comprising the "ion permeome", are common drug targets, however their roles in cancer remain understudied. Our integrative pan-cancer transcriptome analysis shows that genes encoding the ion permeome are significantly more often highly expressed in specific subsets of cancer samples, compared to pan-transcriptome expectations. To enable target selection, we identified 410 survival-associated IP genes in 33 cancer types using a machine-learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma, the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived glioblastoma cells induces transcriptome-wide changes involving neuron projection and proliferation pathways, impairs cell viability and tumor sphere formation in vitro, perturbs tunneling nanotube dynamics, and extends the survival of glioblastoma-bearing mice. Thus, aberrant activation of genes encoding ion transport proteins appears as a pan-cancer feature defining tumor heterogeneity, which can be exploited for mechanistic insights and therapy development.
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Project description:PurposeN6-methyladenosine (m6A) methylation plays a critical role in diverse biological processes. However, knowledge regarding the constitution of m6A on tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) across cancer types is still lacking. We performed comprehensive immuno-genomic analyses to reveal molecular characterization of the m6A regulators and immune-related genes (IRGs) across TME and TIL heterogeneity.MethodsWe comprehensively analyzed the properties of m6A regulators in genomic profiles from The Cancer Genome Atlas (TCGA) according to expression perturbations of crucial IRGs, CD274, CD8A, GZMA, and PRF1. The four IRGs were proved to be reliable biomarkers of TILs and TME via CIBERSORT and ESTIMATE analyses, and their co-expression relationship was certified by TIMER analysis. Based on their median values, the samples from the pan-cancer tissues (N = 11,057) were classified into eight TME types. The RNA expression levels of 13 m6A regulators were compared across TME subtypes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was also used to classify TME clusters, expression variants of IRGs and m6A regulators were verified among TME clusters. Meanwhile, the correlation between m6A regulators and tumor mutational burden (TMB) were tested. Finally, the impacts of IRGs and TME clusters in clinical characteristics and outcomes were revealed.ResultsCD274, CD8A, GZMA, and PRF1 showed similar TILs' characteristics, of which the level of T cells CD8 and T cells CD4 memory activated are consistent with the expression levels of the four IRGs and higher immune infiltration. Besides, CD274, CD8A, GZMA, and PRF1 were positively correlated with the stromal score or immune score in almost all 33 tumor types. All of four IRGs showed impact between tumor pathological stages or clinical outcomes. Among TME type I to type IV, m6A regulators' expression drift changed from high-level to low-level in ESCA, BLCA, HNSC, CESC, BRCA, and GBM. However among TME type V to type VIII, m6A regulators drew a shift from low-level to high-level expression in CESC, BLCA, ESCA, KIRP, HNSC, BRCA, KIRC, COAD, LAML, GBM, and KICH. In ssGSEA analyses, IRGs' expression levels were elevated with the immune infiltration degree and m6A regulators' expression level varied among three TIL subgroups. With different TMB levels, expression differences of m6A regulators were observed in BLCA, BRCA, COAD, LGG, LUAD, LUSC, STAD, THCA, and UCEC.ConclusionWe identified four crucial IRGs affecting TILs, TME characteristics and clinical parameters. Expression variants of m6A regulators among the subgroups of TME types and ssGSEA clusters suggested that m6A regulators may be essential factors for phenotypic modifications of IRGs and thus affecting TME characteristics across multiple tumor types.
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