Dataset Information

METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m⁶A) is implicated in various stages of cancer development. However, a thorough understanding of m⁶A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m⁶A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m⁶A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m⁶A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m⁶A and lncRNA in ccRCC for the first time.

SUBMITTER: Shen D

PROVIDER: S-EPMC8738955 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.

Shen Danyang D Ding Lifeng L Lu Zeyi Z Wang Ruyue R Yu Chenhao C Wang Huan H Zheng Qiming Q Wang Xuliang X Xu Wanjiang W Yu Haifeng H Xu Liwei L Wang Mingchao M Yu Shicheng S Zhu Shibin S Qian Jun J Xia Liqun L Li Gonghui G

Molecular therapy. Nucleic acids 20211217

Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m<sup>6</sup>A) is implicated in various stages of cancer development. However, a thorough understanding of m<sup>6</sup>A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumo ...[more]

PMID: 35036065

Similar Datasets

Project description:Therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase-like 14 (METTL14) can suppress ccRCC development through the modification of N6-methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein 14 (ZFP14) as a novel target of METTL14-mediated m6A, and its under-expression was associated with ccRCC tumourigenesis and progression. Detailed investigations revealed that METTL14 interacted directly with the 3' untranslated region of ZFP14 mRNA, promoting m6A modification at two specific sites. These modifications were recognised by the protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which stabilised and enhanced the expression of ZFP14 mRNA. Functionally, the METTL14/ZFP14 axis suppressed in vitro growth, migration and invasiveness and in vivo proliferation and metastasis of ccRCC cells. ZFP14 potentially regulated numbers of transcripts, among which matrix metalloproteinase 1/3 (MMP1/3) were validated to be under-expressed by ZFP14. Crucially, ZFP14 interacted with the signal transducer and activator of transcription 3 (STAT3), augmenting its K48-linked ubiquitination and destabilising it via the proteasome pathway. Moreover, ZFP14 repressed ccRCC cell in vivo growth and metastasis as well as decreasing MMP1/3 levels by under-expressing STAT3. These observations confirmed that ZFP14 served as both a novel target for METTL14-mediated m6A modification and a significant tumour suppressor in ccRCC, shedding light on the cellular and molecular operations in ccRCC and opening up possibilities for novel therapeutic strategies. KEY POINTS: ZFP14 under-expression is associated with ccRCC tumourigenesis and progression. METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC. ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.

Project description:Diabetic kidney disease (DKD) is a prevalent complication associated with diabetes in which podocyte dysfunction significantly contributes to the development and progression of the condition. Ring finger protein 183 (RNF183) is an ER-localized, transmembrane ring finger protein with classical E3 ligase activity. However, whether RNF183 is involved in glomerular podocyte dysfunction, which is the mechanism of action of DKD, is still poorly understood. In this study, we first demonstrated that RNF183 expression in glomerular podocytes of patients with DKD decreased as the disease progressed. Additionally, our transcriptome sequencing analysis of kidney tissues from diabetic mice revealed a significant reduction in RNF183 expression within the kidney cortex. Similarly, the expression of RNF183 was significantly reduced both in the kidneys of diabetic mice and in human podocytes exposed to high glucose conditions. The downregulation of RNF183 resulted in a suppression of autophagic activity, an increase in apoptotic cell death, and reduced expression of cellular markers in HPC cells. We found that RNF183 was modified via N6-methyladenosine (m6A) RNA methylation. Meanwhile, treatment with meclofenamic acid 2 (MA2), an m6A demethylase inhibitor, resulted in the upregulation of RNF183 expression in HPC cells cultured in high glucose conditions. Furthermore, high glucose treatment decreased the transcription and protein levels in both the m6A writer methyltransferaselike3 (METTL3) and the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). IGF2BP2 assisted with METTL3, which is jointly involved in the transcription of RNF183. Furthermore, we confirmed that RNF183 directly ubiquitinates M2 pyruvate kinase (PKM2) through co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometry (LC-MS) experiments. The level of PKM2 ubiquitination was increased following RNF183 overexpression, leading to enhanced PKM2 protein degradation and subsequently alleviating high glucose-induced podocyte damage. The results of this study indicated that RNF183 was regulated via m6A methylation modification and that RNF183 expression was reduced in HPC cells treated with high glucose, which resulted in decreased PKM2 ubiquitination levels and subsequently aggravated podocyte injury. The findings suggest that RNF183 may serve as a potential therapeutic target for diabetic kidney injury, offering new insights into its role in the progression of DKD.

Project description:BackgroundHemorrhoids are a frequently-occurring disease of the anorectal system that is often accompanied by vascular hyperplasia and edema. A METTL14-mediated RNA N-6 methyladenosine (m6A) modification can improve mRNA stability and increase its transcriptional and translational activities, closely related to the occurrence of many diseases.MethodsWestern blot, qPCR, and immunofluorescence staining were used to detect the levels of gene and protein expression. Haematoxylin and eosin staining was used for histopathological examination. RNA immunoprecipitation-PCR and RNA dot blotting were used to detect mRNA m6A modification.ResultsObvious signs of angiogenesis (CD31+/vWF+) were identified in the hemorrhoids. High levels of METTL14 expression on vascular endothelial cells (CD31+) suggested that angiogenesis was accompanied by differential modification of m6A RNA. It was subsequently found that the level of miR-4729 expression was significantly decreased in hemorrhoid tissues. The luciferase reporter enzyme assay results suggested that miR-4729 silenced its expression by targeting the 3'UTR of METTL14 mRNA. MiR-4729 overexpression in human umbilical vein endothelial cells (HUVECs) inhibited the proliferation and migration of HUVECs in vitro and vascular structure formation in the outer matrix. MiR-4729 overexpression significantly inhibited endogenous METTL14 expression in HUVECs and reduced the entire m6A RNA modification, especially the level of m6A methylation at the specific site of the 3' UTR of TIE1 mRNA. Moreover, miR-4729 overexpression significantly inhibited the molecular loop of the TIE1/VEGFA signaling pathway in HUVECs.ConclusionsOur findings confirmed that the down-regulation of miR-4729 in hemorrhoid vascular endothelial cells was one of the main reasons for vascular proliferation. The overexpression of miR-4729 in vascular endothelial cells decreased the global mRNA methylation and TIE1 mRNA 3'UTR-specific site methylation by silencing METTL14 expression, reducing TIE1 mRNA stability, down-regulating the TIE1/VEGFA signal molecular loop expression, and weakening angiogenesis ability.

Dataset Information

METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.

Publications

METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets