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BTG2 suppresses renal cell carcinoma progression through N6-methyladenosine.

ABSTRACT: The biological functions of N6-methyladenosine (m⁶A) modification of mRNA have recently received a great deal of attention. In previous studies, m⁶A methylation modification has been shown to regulate mRNA fate and to be crucial for the progression and development of tumors. BTG2 (B-cell translocation gene 2) is a member of BTG/TOB anti-proliferative protein family. BTG2 could inhibit cell proliferation and migration and regulate the cell cycle progression. In this study, we confirm that BTG2 is frequently down-regulated in renal cell carcinoma (RCC) tissues and its low expression is associated with unfavorable prognosis and decreased m⁶A level. Moreover, we found that m⁶A methylation modifies the 5'UTR of BTG2 to promote its mRNA stability by binding to IGF2BP2. It has been shown that CRISPR/dCas13b-METLL3 can specifically increase BTG2 m⁶A modification to significantly increase its m⁶A and expression levels. Then m⁶A hypermethylation in BTG2 mRNA could dramatically inhibit RCC cells proliferation and migration, and induce cells apoptosis. Taken together, our data show that BTG2 functions as a tumor suppressor and is frequently silenced via m⁶A modification in RCC.

SUBMITTER: Qi F

PROVIDER: S-EPMC9795213 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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BTG2 suppresses renal cell carcinoma progression through N6-methyladenosine.

Qi Fuming F Liu Wenlong W Tan Bo B Zhang Juan J Ma Yan Y Cao Congcong C Ma Fujun F Zhu Bo B Yang Jinhui J Liu Xiaoyun X

Frontiers in oncology 20221214

The biological functions of N6-methyladenosine (m<sup>6</sup>A) modification of mRNA have recently received a great deal of attention. In previous studies, m<sup>6</sup>A methylation modification has been shown to regulate mRNA fate and to be crucial for the progression and development of tumors. BTG2 (B-cell translocation gene 2) is a member of BTG/TOB anti-proliferative protein family. BTG2 could inhibit cell proliferation and migration and regulate the cell cycle progression. In this study, w ...[more]

PMID: 36591524

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Project description:BackgroundStudies on biological functions of N6-methyladenosine (m6 A) modification in mRNA have sprung up in recent years. Previous studies have reported m6 A can determine mRNA fate and play a pivotal role in tumour development and progression. The zinc finger protein 677 (ZNF677) belongs to the zinc finger protein family and possesses transcription factor activity by binding sequence-specific DNA.MethodsThe expression of ZNF677 and its clinicopathological impact were evaluated in renal cell carcinoma (RCC) patients. The m6 A level of ZNF677 was determined by m6 A methylated RNA immunoprecipitation-sequencing (MeRIP-seq) and MeRIP-qPCR in RCC tissues and adjacent normal tissues. RNA immunoprecipitation-qPCR (RIP-qPCR) and luciferase assays were performed to identify the targeted effect of IGF2BP2 and YTHDF1 on ZNF677. RCC cells and subcutaneous models uncovered the role of ZNF677 methylated by CRISPR/dCas13b-METTL3 in tumour growth. ZNF677-binding sites in the CDKN3 promoter were investigated by chromatin immunoprecipitation (ChIP) and luciferase assays.ResultsZNF677 is frequently downregulated in RCC tissues and its low expression is associated with unfavourable prognosis and decreased m6 A modification level. Further, we find the m6 A-modified coding sequence (CDS) of ZNF677 positively regulates its translation and mRNA stability via binding with YTHDF1 and IGF2BP2, respectively. Targeted specific methylation of ZNF677 m6 A by CRISPR/dCas13b-METLL3 system can significantly increase the m6 A and expression level of ZNF677, and dramatically inhibit cell proliferation and induce cell apoptosis of RCC cells. In addition, ZNF677 exerted its tumour suppressor functions in RCC cells through transcriptional repression of CDKN3 via binding to its promoter. In vitro and clinical data confirm the negative roles of ZNF677/CDKN3 in tumour growth and progression of RCC.ConclusionZNF677 functions as a tumour suppressor and is frequently silenced via m6 A modification in RCC, which may highlight m6 A methylation-based approach for RCC diagnosis and therapy.

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.

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.

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BTG2 suppresses renal cell carcinoma progression through N6-methyladenosine.

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BTG2 suppresses renal cell carcinoma progression through N6-methyladenosine.

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