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

Abstract

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...

Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway

“…In the process of cancer, RBP regulates the expression of many important genes post-transcriptionally by altering its encoded mRNA. Previous studies have shown that Mex3a regulates CDX2 in human colon cancer and promoted proliferation in gastric cancer and glioblastoma 2,4,18 . Here, for the first time, we identified that Mex3a was upregulated in human LUAD and high Mex3a expression correlated with positive lymph node metastasis, and advanced TNM stage, suggesting that Mex3a can be a strong predictor for LUAD metastasis and prognosis.…”

The Stemness Gene Mex3A Is a Key Regulator of Neuroblast Proliferation During Neurogenesis

“…Mex3A appears crucial for the maintenance of the slowly cycling subpopulation of lgr5+ gut stem cells (Chatterji and Rustgi, 2018), and lgr5 absence in Mex3A −/− mice leads to growth retardation, postnatal mortality, and severe impairment of intestinal crypt development (Pereira et al, 2020). Recent data showed that MEX3A is up-regulated in glioblastoma specimens (Bufalieri et al, 2020). In glioblastoma cells, MEX3A interacts with the tumor suppressor RIG-I inducing its ubiquitinylation and the proteasome-dependent degradation, supporting tumor growth (Bufalieri et al, 2020).…”

“…Recent data showed that MEX3A is up-regulated in glioblastoma specimens (Bufalieri et al, 2020). In glioblastoma cells, MEX3A interacts with the tumor suppressor RIG-I inducing its ubiquitinylation and the proteasome-dependent degradation, supporting tumor growth (Bufalieri et al, 2020). Although MEX3A has a key role in gastrointestinal homeostasis and tumor progression, its putative role in neural context is not yet defined.…”

“…Several neural-specific RNA-binding proteins are key inducers of neuronal proliferation and/or differentiation through the stabilization and/or translational enhancement of target transcripts. Additionally, Mex3A seems to have an important role as post-translational regulators also acting as E3 ubiquitin ligase in glioblastoma cells (Bufalieri et al, 2020).…”

“…In mice, mex3A is expressed in the crypt base and labels a slowly cycling subpopulation of Lgr5+ intestinal stem cell population (Barriga et al, 2017;Chatterji and Rustgi, 2018). MEX3A is overexpressed in pancreatic ductal adenocarcinoma (Wang et al, 2020) and strongly up-regulated in glioblastoma samples (Bufalieri et al, 2020). Despite this evidence, to our knowledge, there are no data available regarding the putative role of mex3a during embryonic and adult neurogenesis.…”