Publisher Correction: N6-methyladenosine-modified ALDH9A1 modulates lipid accumulation and tumor progression in clear cell renal cell carcinoma through the NPM1/IQGAP2/AKT signaling pathway.
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SUBMITTER: Tan D
PROVIDER: S-EPMC11362545 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
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Publisher Correction: N6-methyladenosine-modified ALDH9A1 modulates lipid accumulation and tumor progression in clear cell renal cell carcinoma through the NPM1/IQGAP2/AKT signaling pathway.
Tan Diaoyi D Miao Daojia D Zhao Chuanyi C Shi Jian J Lv Qingyang Q Lu Feiyi F Ruan Hailong H Xiong Zhiyong Z Zhang Xiaoping X
Cell death & disease 20240829 8
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Project description:Aldehyde dehydrogenases superfamily (ALDHs), which are ubiquitously present in various organisms with diverse subcellular localizations, play a crucial role in regulating malignant tumor progression; Nevertheless, their involvement in clear cell renal cell carcinoma (ccRCC) has not been elucidated. In this study, we performed comprehensive bioinformatics analyses on the 19 ALDHs genes, and identified ALDH9A1 as a key contributor in ccRCC. Expression patterns and clinical relevance of ALDH9A1 were determined using bioinformatics analyses, real-time PCR, western blotting, and immunohistochemistry. To explore the underlying mechanism behind the tumor suppressor role of ALDH9A1, RNA sequencing, methylated RNA immunoprecipitation, luciferase reporter assay, mass spectroscopy, immunoprecipitation, mutational studies and immunofluorescence were employed. The impact of ALDH9A1 in ccRCC progression and metabolic programming was assessed through both in vitro and in vivo. Here, this study revealed ALDH9A1 as a tumor suppressor gene in ccRCC. The fat mass and obesity associated protein (FTO) was identified as a demethylase for ALDH9A1 mRNA, resulting in its reduced stability and expression levels in ccRCC. Functional experiments demonstrated that the deficiency of ALDH9A1 in ccRCC promoted tumor proliferation, invasion, migration and lipid accumulation. Mechanistic insights illustrated that the diminished levels of ALDH9A1 resulted in the failure to sequester nucleophosmin 1 (NPM1) within cytoplasm, thereby suppressing the transcription of IQ motif containing the GTPase-activating protein 2 (IQGAP2), subsequently activating the AKT-mTOR signaling, ultimately fostering tumor progression and lipid accumulation. In conclusion, the present study highlights the robust prognostic significance of ALDH9A1 and delivers a comprehensive understanding of ALDH9A1-NPM1-IQGAP2-AKT axis in ccRCC. These findings established a solid research foundation for novel therapeutic strategies for ccRCC patients.
| S-EPMC11263707 | biostudies-literature
Project description:Succinylation is a newly discovered and multienzyme-regulated post-translational modification (PTM) that is associated with the initiation and progression of cancer. Currently, no systematic analyses on the role of succinylation regulators in tumors have been reported. In this study, we performed a comprehensive pan-cancer analysis on four well-known succinylation regulators (CPT1A, KAT2A, SIRT5, and SIRT7). We found that these regulators played specific and critical roles in the prognosis of clear cell renal cell carcinoma (ccRCC). We constructed a risk score (RS) based on two independent prognostic prediction factors, CPT1A and KAT2A, and subsequently developed a nomogram model containing the RS, which showed good accuracy in the prediction of overall survival (OS) in ccRCC patients. Furthermore, we used the similar expression pattern of four succinylation regulators according to consensus clustering analysis to divide the patients into three clusters that exhibited prominently different OS as well as clinicopathological characteristics. Differently expressed genes (DEGs) and pathway enrichment analyses of three clusters indicated that succinylation regulators might promote malignant progression of ccRCC by regulating the infiltration of immune cells and RNA N6-methyladenosine (m6A) methylation. Importantly, our data suggest that CPT1A and SIRT5 might up-regulate and down-regulate the expression of LRPPRC and EIF3B, respectively. Our study systematically analyzed the prognostic predictive values of four succinylation regulators and revealed their potential mechanisms in ccRCC aggressiveness. These data provide new insight into the understanding of succinylation modification and present clinical evidence for its role in ccRCC treatments.
| S-EPMC7935513 | biostudies-literature
Project description:BackgroundClear-cell renal-cell carcinoma (ccRCC) is one of the leading causes of tumour-related death worldwide. Methyltransferase-like 14 (METTL14) is reported to regulate m6A modification in cancers. The aim of this study is to investigate the biological function and molecular mechanism of METTL14 in the pathogenesis of ccRCC.MethodsQuantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were used to detect the expression of METTL14 and Pten. METTL14 overexpression or knockdown was used in the in vitro and in vivo studies to investigate the biological functions of METTL14. m6A-RNA immunoprecipitation and RNA immunoprecipitation were used to investigate the m6A modification mediated by METTL14.ResultsMETTL14 expression was significantly down-regulated in ccRCC tissues. Functionally, upregulation of METTL14 inhibited ccRCC cells proliferation and migration in vitro. METTL14 overexpression significantly inhibited the activation of the phosphoinositide 3 kinase (PI3K)/AKT signalling pathway. Furthermore, phosphate and tension homology deleted on chromosome ten (Pten) is a target of METTL14. Overexpression of METTL14 increased the m6A enrichment of Pten, and promoted Pten expression. METTL14-enhanced Pten mRNA stability was dependent on YTHDF1.ConclusionsMETTL14-mediated m6A modification of Pten mRNA inhibited tumour progression, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for ccRCC.
| S-EPMC9276773 | biostudies-literature
Project description:The abundant and reversible N6-methyladenosine (m6A) RNA modification and its modulators have important roles in regulating various gene expression and biological processes. Here, we demonstrate that fat mass and obesity associated (FTO), as an m6A demethylase, plays a critical anti-tumorigenic role in clear cell renal cell carcinoma (ccRCC). FTO is suppressed in ccRCC tissue. The low expression of FTO in human ccRCC correlates with increased tumour severity and poor patient survival. The Von Hippel-Lindau-deficient cells expressing FTO restores mitochondrial activity, induces oxidative stress and ROS production and shows impaired tumour growth, through increasing expression of PGC-1α by reducing m6A levels in its mRNA transcripts. Our work demonstrates the functional importance of the m6A methylation and its modulator, and uncovers a critical FTO-PGC-1α axis for developing effective therapeutic strategies in the treatment of ccRCC.
| S-EPMC6378205 | biostudies-literature
Project description:RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of VHL followed by mutations in epigenetic regulators PBRM1, SETD2, and BAP1. Mutations in SETD2, a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming. While m6A and H3K36me3 deregulation are separately implicated in renal tumorigenesis, H3K36me3 may participate directly in m6A targeting, but the m6A-H3K36me3 interplay has not been investigated in the context of ccRCC. Using RCC-relevant SETD2 isogenic knockout and rescue cell line models, we demonstrate a dynamic redistribution of m6A in the SETD2 depleted transcriptome, with a subset of transcripts involved in metabolic reprogramming demonstrating SETD2 dependent m6A and expression level changes. Using a panel of six histone modifications we show that m6A redistributes to regions enriched in gained active enhancers upon SETD2 inactivation. Finally, we demonstrate a reversal of transcriptomic programs involved in SETD2 loss mediated metabolic reprogramming, and reduced cell viability through pharmacologic inhibition or genetic ablation of m6A writer METTL3 specific to SETD2 deficient cells. Thus, targeting m6A may represent a novel therapeutic vulnerability in SETD2 mutant ccRCC.
| S-EPMC11776469 | biostudies-literature
Project description:BackgroundAlthough the RNA modification N6-methyladenosine ZC3H13 has been found to play vital regulatory roles in many types of cancers, its role in predicting the tumor immune microenvironment (TME) and response to immune checkpoint blockade (ICB) in kidney renal clear cell carcinoma (KIRC) remains unclear.MethodsWe comprehensively analyzed the expression, prognostic significance and immunological role of ZC3H13 in pan-cancers and systematically correlated ZC3H13 with TME cell-infiltration, ICB response and targeted therapy in KIRC. The data were collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), Broad Institute Cancer Cell Line Encyclopedia (CCLE) and DrugBank database. Also, we performed RNA sequencing (RNA-seq) of 46 renal cell carcinoma tissues and 11 adjacent normal tissues to validate our result. All analyses were implemented using R software, version 3.6.3.ResultsZC3H13 was significantly differentially expressed in most tumors. However, its expression profiles and prognostic significance were consistent only in KIRC, regardless of overall survival, progression-free survival and cancer-specific survival. Additionally, ZC3H13 expression was correlated with clinicopathological factors in KIRC. Furthermore, we found that ZC3H13 might shape a noninflamed phenotype and could predict a lower response to ICB in KIRC. These results could be validated in our own RNA-seq data. Tumor mutation burden (TMB) was significantly higher in the low ZC3H13 group. Finally, we found that ZC3H13 could predict the sensitivity of targeted therapy for KIRC.ConclusionsZC3H13 might shape a noninflamed phenotype in KIRC. Moreover, ZC3H13 could predict the prognosis and clinical response of ICB and the sensitivity to targeted therapies in KIRC.
| S-EPMC8420859 | biostudies-literature
Project description:RNA modification of N6-methyladenosine (m6A) plays critical roles in various biological processes, such as cancer development, inflammation, and the anticancer immune response. However, the role played by a comprehensive m6A modification pattern in regulating anticancer immunity in kidney renal clear cell carcinoma (KIRC) has not been fully elucidated. In this study, we identified two independent m6A modification patterns with distinct biological functions, immunological characteristics, and prognoses in KIRC. Next, we developed an m6A score algorithm to quantify an individual's m6A modification pattern, which was independently validated in external cohorts. The m6A cluster 1 and low m6A score groups were characterized by a hot tumor microenvironment with an increased infiltration level of cytotoxic immune cells, higher tumor mutation burden, higher immune checkpoint expression, and decreased stroma-associated signature enrichment. In general, the m6A cluster 1 and low m6A score groups reflected an inflammatory phenotype, which may be more sensitive to anticancer immunotherapy. The m6A cluster 2 and high m6A score groups indicated a non-inflammatory phenotype, which may not be sensitive to immunotherapy but rather to targeted therapy. In this study, we first identified m6A clusters and m6A scores to elucidate immune phenotypes and to predict the prognosis and immunotherapy response in KIRC, which can guide urologists for making more precise clinical decisions.
| S-EPMC8013979 | biostudies-literature
Project description:N6‑methyladenosine (m6A) RNA methylation is the most prevalent type of mRNA modification; however, little is known about its function in clear cell renal cell carcinoma (ccRCC). The present study aimed to establish and validate a m6A‑related risk signature as a prognostic factor for patients with ccRCC. Consensus clustering was used to divide patients with ccRCC from The Cancer Genome Atlas (TCGA) cohort (n=489) into three clusters (cluster 1/2/3) based on 19 m6A RNA methylation regulators. In addition, a m6A‑related risk signature was constructed using TCGA data, and its accuracy was validated using data from the International Cancer Genome Consortium (n=91). The prognostic performance of the risk signature was evaluated by Kaplan‑Meier analyses, least absolute shrinkage and selection operator Cox regression, multivariate Cox regression, receiver operating characteristic curves and nomograms. The results revealed that the majority of the 19 m6A RNA methylation regulators were differentially expressed among ccRCC stratified by different clinicopathological features. The cluster 1 group exhibited a higher frequency of metastasis and poorer overall survival compared with the cluster 2/cluster 3 group. The hallmarks of RNA metabolism, transcription misregulation in cancer and regulation of autophagy, were significantly enriched in the cluster 1 group. A m6A‑related risk signature was constructed and validated with high prognostic accuracy for the prediction of 5‑year survival and recurrence (area under the curve, 0.736 and 0.728, respectively). The present study also established robust nomograms for evaluating the risk of mortality and recurrence for patients with ccRCC (c‑index, 0.783 and 0.819, respectively). The dysregulation of hub m6A RNA methylation regulator expression levels and m6A RNA methylation levels were also validated in multiple RCC cells using in vitro experiments. Taken together, the m6A RNA methylation regulators promoted the malignant progression of ccRCC and exhibited good performance in prognostic predictions. These results provided insight into the development of m6A‑targeted treatments for ccRCC.
| S-EPMC7108075 | biostudies-literature
Project description:BackgroundKidney renal clear cell carcinoma (KIRC) lacks effective prognostic biomarkers and the role and mechanism of N6-methyladenosine (m6A) modification of long noncoding RNAs (lncRNAs) in KIRC remain unclear.MethodsWe extracted standard mRNA-sequencing and clinical data from the TCGA database. The prognostic risk model was obtained by Lasso regression and Cox regression. We randomly divided the samples into training and test sets, each taking half of the cases. Based on Lasso regression and Cox regression for training set, the prognostic risk signature was constructed; risk scores were calculated with the R package "glmnet." Based on the median value of the prognostic risk score, risk scores were calculated for each patient and we divided all KIRC samples into high-risk and low-risk groups. Then, high- and low-risk subtypes were established and their prognosis, clinical features, and immune infiltration microenvironment were evaluated in test set and the entire sampled data set. The reliability of the prognostic model was confirmed by receiver operating characteristic curve analysis.ResultsWe found 28 prognostic m6A-related lncRNAs and established a m6A-related lncRNAs prognostic signature. Risk score=AC015813.1∗(0.0086)+EMX2OS∗(-0.0101)+LINC00173∗(0.0309)+PWAR5∗(-0.0146)+SNHG1∗(0.0043). The signature showed a better predictive ability than other clinical indicators, including tumor node metastasis classification (TNM), histological, and pathological stages. In the high-risk group, M0 macrophages, CD8+ T cells, and regulatory T cells had significantly higher scores. Contrarily, in the low-risk group, activated dendritic cells, M1 macrophages, mast resting cells, and monocytes had significantly higher scores. In the high-risk group, LSECtin was overexpressed. In the low-risk group, PD-L1 was overexpressed. Moreover, high-risk patients may benefit more from AZ628.ConclusionsIn conclusion, prognosis prediction of patients with KIRC and new insights for immunotherapy are provided by the m6A-related lncRNA prognostic signature.
| S-EPMC9536954 | biostudies-literature
Project description:Increasing evidence suggests that N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play important roles in cancer progression and immunotherapeutic efficacy in clear-cell renal cell carcinoma (ccRCC). In this study, we conducted a comprehensive ccRCC RNA-seq analysis using The Cancer Genome Atlas data to establish an m6A-related lncRNA prognostic signature (m6A-RLPS) for ccRCC. Forty-four prognostic m6A-related lncRNAs (m6A-RLs) were screened using Pearson correlation analysis (|R| > 0.7, p < 0.001) and univariable Cox regression analysis (p < 0.01). Using consensus clustering, the patients were divided into two clusters with different overall survival (OS) rates and immune status according to the differential expression of the lncRNAs. Gene set enrichment analysis corroborated that the clusters were enriched in immune-related activities. Twelve prognostic m6A-RLs were selected and used to construct the m6A-RLPS through least absolute shrinkage and selection operator Cox regression. We validated the differential expression of the 12 lncRNAs between tumor and non-cancerous samples, and the expression levels of four m6A-RLs were further validated using Gene Expression Omnibus data and Lnc2Cancer 3.0 database. The m6A-RLPS was verified to be an independent and robust predictor of ccRCC prognosis using univariable and multivariable Cox regression analyses. A nomogram based on age, tumor grade, clinical stage, and m6A-RLPS was generated and showed high accuracy and reliability at predicting the OS of patients with ccRCC. The prognostic signature was found to be strongly correlated to tumor-infiltrating immune cells and immune checkpoint expression. In conclusion, we established a novel m6A-RLPS with a favorable prognostic value for patients with ccRCC. The 12 m6A-RLs included in the signature may provide new insights into the tumorigenesis and allow the prediction of the treatment response of ccRCC.
| S-EPMC8554127 | biostudies-literature