Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond

Cai, Haijian; Zheng, Dandan; Yao, Yizhu; Yang, Lehe; Huang, Xiaoying; Wang, Liangxing

doi:10.3389/fcell.2022.847761

Cited by 6 publications

(5 citation statements)

References 145 publications

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“…4d and e ). A significant decrease in several forms of RPS6 (S240, S235, S244), RAF1 S621, ELAVL1 S202, and EIF4EBP1 T70 is also compatible with impaired cancer cell proliferation observed under stress 44–47 . These alterations are consistent with the adoption of more aggressive phenotypes by microenvironment challenged cells.…”

Section: Resultsmentioning

confidence: 85%

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

Peixoto,

Ferreira,

Miranda

et al. 2023

Preprint

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Bladder tumours with aggressive characteristics often present with microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose-deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid β-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation, providing grounds for clinical intervention.

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Section: Resultsmentioning

confidence: 85%

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

Peixoto,

Ferreira,

Miranda

et al. 2023

Preprint

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“…The specific transcript binding and activity of each ELAV family member creates unique neuronal transcriptomic signatures. Such specificity between paralogues is also observed in other species, where studying the ELAV paralogues has helped gain knowledge into the cellular and developmental activities of these proteins [ 14 , 40 , 41 ].…”

Section: Elav Was First Identified In Drosophila Melanogastermentioning

confidence: 87%

The molecular genetics of nELAVL in brain development and disease

Mulligan,

Bicknell

2023

Eur J Hum Genet

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Embryonic development requires tight control of gene expression levels, activity, and localisation. This control is coordinated by multiple levels of regulation on DNA, RNA and protein. RNA-binding proteins (RBPs) are recognised as key regulators of post-transcriptional gene regulation, where their binding controls splicing, polyadenylation, nuclear export, mRNA stability, translation rate and decay. In brain development, the ELAVL family of RNA binding proteins undertake essential functions across spatiotemporal windows to help regulate and specify transcriptomic programmes for cell specialisation. Despite their recognised importance in neural tissues, their molecular roles and connections to pathology are less explored. Here we provide an overview of the neuronal ELAVL family, noting commonalities and differences amongst different species, their molecular characteristics, and roles in the cell. We bring together the available molecular genetics evidence to link different ELAVL proteins to phenotypes and disease, in both the brain and beyond, including ELAVL2, which is the least studied ELAVL family member. We find that ELAVL-related pathology shares a common neurological theme, but different ELAVL proteins are more strongly connected to different phenotypes, reflecting their specialised expression across time and space.

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“…As the most frequent malignant tumor of the central nervous system, GBM’s prognosis is very poor, and the median survival time is even <15 months. The comprehensive treatment effect represented by surgery combined with radiotherapy and chemotherapy is not ideal [ 13 ]. Based on the role of oncogenes and tumor suppressor genes, molecular targeted therapy was proposed and has become the most promising way to cure malignant tumors, such as bevacizumab, a targeted inhibitor for VEGF, or trastuzumab, a targeted inhibitor for HER2, etc.…”

Section: Discussionmentioning

confidence: 99%

“…RNA binding proteins (RBPs) are proteins that can actively bind circRNAs, regulating their back-splicing and synthesis, stability and degradation, intracellular distribution, and so on [ 13 ]. Our previous studies found that RBP FMR1 can maintain the stability of circCHAF1A and upregulate its expression in GSCs [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

CircKPNB1 mediates a positive feedback loop and promotes the malignant phenotypes of GSCs via TNF-α/NF-κB signaling

et al. 2022

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Glioma stem cells (GSCs) are a special kind of cells in GBM showing tumor initiation, self-renewal, and multi-lineage differentiation abilities. Finding novel circRNAs related to GSCs is of great significance for the study of glioma. qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of circKPNB1, SPI1, DGCR8, and TNF-α. The expression of these molecules in GSCs was regulated by lentiviral-based infection. RNA immunoprecipitation assay, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to study the direct regulation mechanisms among these molecules. All the MTS, EDU, transwell, neurosphere formation assays, ELDA assays, and xenograft experiments were used to detect the malignant phenotype of GSCs. We found a novel circRNA circKPNB1 was overexpressed in GBM and associated with GBM patients’ poor prognosis. CircKPNB1 overexpression can promote the cell viabilities, proliferation, invasion, neurospheres formation abilities, and stemness of GSCs. Mechanistically, circKPNB1 regulates the protein stability and nuclear translocation of SPI1. SPI1 promotes the malignant phenotype of GSCs via TNF-α mediated NF-κB signaling. SPI1 can also transcriptionally upregulate DGCR8 expression, and the latter can maintain the stability of circKPNB1 and forms a positive feedback loop among DGCR8, circKPNB1 and SPI1. Our study found circKPNB1 was a novel oncogene in GBM and of great significance in the diagnosis and prognosis prediction of GBM and maybe a novel target for molecular targeted therapy.

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Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond

Cited by 6 publications

References 145 publications

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

The molecular genetics of nELAVL in brain development and disease

CircKPNB1 mediates a positive feedback loop and promotes the malignant phenotypes of GSCs via TNF-α/NF-κB signaling

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