HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells

Xue, Min; Chen, Lu-yi; Wang, Weijia; Su, Tingting; Shi, Liuhong; Wang, Lan; Zhang, Wen; Si, Jianmin; Wang, Liang-jing; Chen, Shujie

doi:10.1007/s10120-018-0801-6

Cited by 61 publications

(50 citation statements)

References 24 publications

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“…Here, we described for the first time that the RNA-binding MEX3A affects GB proliferation, acting as an E3-ubiquitin ligase. So far, little is known about the role of this protein in carcinogenesis [21][22][23][24]26]. Although MEX3A is a member of the RNA-binding ubiquitin ligase MEX3 protein family, its function as E3-ligase and its potential substrates have not yet been described.…”

Section: Discussionmentioning

confidence: 99%

“…MEX3 proteins play pivotal role in self-renewal and differentiation processes, with implications regarding stemness and carcinogenesis [20][21][22][23][24][25]. In particular, alterations of MEX3A activity have been described in gastric, colorectal and bladder cancers, although its mechanism of action and its potential substrates remain still elusive [21][22][23][24]26]. To date, only the RING finger domain of human MEX3C has been functionally and structurally characterized, and Retinoic acid-inducible gene I (RIG-I) is the unique substrate described for this E3 ligase [27].…”

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confidence: 99%

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The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Bufalieri

Caimano

Severini

et al. 2020

Cancers

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Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB.Cancers 2020, 12, 321 2 of 16 treatments [2]. The current therapeutic protocol for GB patients consists of surgical resection of tumor mass and subsequent concomitant radiotherapy and chemotherapy. However, these approaches show very limited effectiveness, resulting in a high rate of relapse and subsequent deterioration of the patient's neurological and physiological status [2,5].In the recent years, several genetic and epigenetic aberrations in molecular pathways (i.e., WNT and Hedgehog signaling) [6-9] have been associated with GB onset and progression, representing potential therapeutic targets and biomarkers for early prognosis [2,3,5]. Hence, the identification and characterization of new molecular players involved in GB tumorigenesis is essential for developing more effective and innovative therapies against this aggressive malignancy.Ubiquitylation is a post-translational modification that controls a wide range of cellular functions (i.e., protein degradation, endocytosis and trafficking) and the most important physiological processes [10,11]. Ubiquitylation is mediated by an enzymatic cascade, in which the E3-ubiquitin ligases are the main players, responsible for the recognition of specific substrates and the final transferring of ubiquitin moieties onto target proteins.Deregulation or mutations of E3-ubiquitin ligases have been associated with several human tumors; for this reason, they are considered to be promising targets for novel anticancer therapies [12][13][14]. At present, very little information is available about the role of E3 ligases and ubiquitylation processes in GB development and progression [15][16][17].In this regard, we evaluated the expression levels of catalytic E3-ubiquitin ligase complex components [18] and F-b...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Bufalieri

Caimano

Severini

et al. 2020

Cancers

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“…To understand the internal contact between lncRNA-miRNA-mRNA in the development and progression of GC, the present study constructed the ceRNA network by bioinformatics prediction based on differences in lncRNA, miRNA and mRNA expression from TCGA. Certain lncRNAs that exist in the network have been proven to interact with miRNA and mRNA and may be potential biomarkers in the diagnosis, therapy and prognosis of GC, including UCA1, HOTTIP, HOTAIR and H19 (45)(46)(47)(48). Additionally, a few genes from the ceRNA network, including CHRDL1, COL1A1, HOXC8 and ATAD2, have been reported to act as tumor oncogenes or suppressor genes, participating in tumor growth, invasion and metastasis (41,(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

TCGA dataset‑based construction and integrated analysis of aberrantly expressed long non‑coding RNA mediated competing endogenous RNA network in gastric cancer

Zhang

et al. 2018

Oncol Rep

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The aberrant expression of long non-coding RNAs (lncRNAs) has been confirmed to play a pivotal role in tumor initiation and development. LncRNAs can interact with microRNAs (miRNAs) as competing endogenous RNAs (ceRNAs) to regulate the expression of target genes in various cancers. In the present study, the authors investigated the functions of lncRNAs as ceRNAs in gastric cancer (GC) and their implications for the prognosis. The RNA sequencing profiles of 372 tumor samples and 32 adjacent non-tumor gastric samples were downloaded from The Cancer Genome Atlas (TCGA) database. The differential expression of RNAs was identified using the ʻedgeRʼ package in R language software. Survival analysis was estimated based on Kaplan-Meier curves. The Gene Ontology biological processes and the Kyoto Encyclopedia of Genes and Genomes pathways were analyzed for differentially expressed mRNAs. Finally, a total of 999 lncRNAs, 137 miRNAs and 1629 mRNAs were identified as differentially expressed (DE) in GC with log fold change (FC) thresholds >2 and adjusted P-values <0.01. A ceRNA network was constructed with 65 DElncRNAs, nine DEmiRNAs and 24 DEmRNAs. Of the 65 DElncRNAs in the ceRNA network, nine were identified to be significantly associated with overall survival (P<0.05). A total of four DElncRNAs from the ceRNA network were validated by reverse transcription-quantitative polymerase chain reaction and revealed to be associated with tumorigenesis and/or progression. In conclusion, the results of the present study provide information on the role of the ceRNA network in GC. These identified novel lncRNAs are potential candidate biomarkers and require further studies.

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“…Runx3 endows gastric cells with the capacity of excessive proliferation and invasion (122). The combination of HOTAIR and Mex3b, a type of E3 ligase possessing RNA binding domains, can attenuate the degradation of Runx3, thus regulating cancer migration and invasion (123). Zeng et al (124) found that LINc00675 could enhance the phosphorylation of vimentin on Ser8 and the p53 signaling pathway.…”

Section: Long Non-coding Rnas (Lncrnas)mentioning

confidence: 99%

“…A novel therapeutic method for Gc relies on the elucidation of the mechanisms responsible for the development of Gc. Previous studies have screened out numerous circRNAs and lncRNAs with therapeutic potential (41)(42)(43)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)115,(118)(119)(120)(121)(123)(124)(125)(126)(127)(128)132,133,138,(140)(141)(142)(143)(144)(145), mainly by small interference in vitro and by inhibition of tumor burden in vivo. Various new signaling pathways were identified, which were connected with established cancer promoters or suppressors.…”

Section: Comparison Of Achievements Regarding Circrnas and Lncrnasmentioning

confidence: 99%

Role of circular RNAs and long non‑coding RNAs in the clinical translation of gastric cancer (Review)

et al. 2020

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Gastric cancer (Gc) is a malignancy with high incidence and mortality rates worldwide. It has a severe impact on patients diagnosed and on society. With the rapid development of bioinformatics and detection technologies, non-coding RNAs have been demonstrated to play important roles in gastric carcinogenesis, including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Previous studies have indicated that these two types of RNAs with notable characteristics can serve as promising biomarkers for clinical diagnosis and prognosis. The identification of relevant mechanisms has revealed the immense potential of circRNAs and lncRNAs in the treatment of Gc. However, there are still numerous issues that need to be resolved. The present review focuses on the clinical translation of circRNAs and lncRNAs into Gc. Important achievements and currently existing limitations in this field of research are summarized from recent studies. The present review also proposes serviceable suggestions for further development.

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HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells

Abstract: These results uncovered the novel interaction between HOTAIR and Runx3, and provided potential therapeutic targets on the metastasis of gastric cancer.

Cited by 61 publications

References 24 publications

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

TCGA dataset‑based construction and integrated analysis of aberrantly expressed long non‑coding RNA mediated competing endogenous RNA network in gastric cancer

Role of circular RNAs and long non‑coding RNAs in the clinical translation of gastric cancer (Review)

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