The versatile role of HuR in Glioblastoma and its potential as a therapeutic target for a multi-pronged attack

Guha, Abhishek; Waris, Saboora; Nabors, Louis B.; Filippova, Natalia; Gorospe, Myriam; Kwan, Thaddaeus; King, Peter H.

doi:10.1016/j.addr.2021.114082

Cited by 15 publications

(31 citation statements)

References 178 publications

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“…The most widely accepted therapeutic approach for GBM is surgery with radiotherapy plus temozolomide, followed by an adjuvant phase with temozolomide alone [ 2 ]. However, the current treatment protocol cannot markedly improve the poor prognosis of GBM patients, [ 3 ] with a median survival of only 15 months [ 4 ]. Energy metabolism reprogramming has been identified as one of ten hallmarks of cancer, [ 5 ] so anti-metabolic therapy has become a new research direction for GBM treatment.…”

Section: Introductionmentioning

confidence: 99%

A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5

Song

Zheng

Liu

et al. 2022

J Exp Clin Cancer Res

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Background RNA-binding proteins (RBPs) and circular RNAs (circRNAs) play important roles in glioblastoma multiforme (GBM). Aerobic glycolysis is a metabolic characteristic of GBM. However, the roles of RBPs and circRNAs in aerobic glycolysis in GBM remain unclear. The aim of this study is to explore the mechanisms by which RBPs and circRNAs regulate aerobic glycolysis in GBM cells. Methods RNA sequencing and circRNA microarray analysis were performed to identify RBPs and circRNAs for further study. Mass spectrometry validated the encoded protein and its interacting proteins. Quantitative reverse transcription PCR and western blot assays were used to determine the mRNA and protein expression, respectively. Furthermore, immunofluorescence and fluorescence in situ hybridization assays were used to determine the protein and RNA localization, respectively. Glucose and lactate measurement assays, Seahorse XF glycolysis stress assays and cell viability assays were conducted to investigate the effects on glycolysis and proliferation in GBM cells. Results We selected zinc finger CCHC-type and RNA-binding motif 1 (ZCRB1) and circRNA HEAT repeat containing 5B (circHEATR5B) as candidates for this study. These genes were expressed at low levels in GBM tissues and cells. Both ZCRB1 and circHEATR5B overexpression suppressed aerobic glycolysis and proliferation in GBM cells. ZCRB1 overexpression promoted the Alu element-mediated formation of circHEATR5B. In addition, circHEATR5B encoded a novel protein HEATR5B-881aa which interacted directly with Jumonji C-domain-containing 5 (JMJD5) and reduced its stability by phosphorylating S361. JMJD5 knockdown increased pyruvate kinase M2 (PKM2) enzymatic activity and suppressed glycolysis and proliferation in GBM cells. Finally, ZCRB1, circHEATR5B and HEATR5B-881aa overexpression inhibited GBM xenograft growth and prolonged the survival time of nude mice. Conclusions This study reveals a novel mechanism of regulating aerobic glycolysis and proliferation in GBM cells through the ZCRB1/circHEATR5B/HEATR5B-881aa/JMJD5/PKM2 pathway, which can provide novel strategies and potential targets for GBM therapy.

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Section: Introductionmentioning

confidence: 99%

A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5

Song

Zheng

Liu

et al. 2022

J Exp Clin Cancer Res

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“…HuR, also known as ELAV1, is an RNA-binding protein. HuR-regulated genes are involved in apoptosis, tumorigenesis, radiotherapy resistance, and hypoxia [ 48 ]. In addition, HuR counteracts the translational repression of STAT3 by binding mRNA [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

ARPC1B promotes mesenchymal phenotype maintenance and radiotherapy resistance by blocking TRIM21-mediated degradation of IFI16 and HuR in glioma stem cells

Gao

Yang

et al. 2022

J Exp Clin Cancer Res

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Background Intratumoral heterogeneity is the primary challenge in the treatment of glioblastoma (GBM). The presence of glioma stem cells (GSCs) and their conversion between different molecular phenotypes contribute to the complexity of heterogeneity, culminating in preferential resistance to radiotherapy. ARP2/3 (actin-related protein-2/3) complexes (ARPs) are associated with cancer migration, invasion and differentiation, while the implications of ARPs in the phenotype and resistance to radiotherapy of GSCs remain unclear. Methods We screened the expression of ARPs in TCGA-GBM and CGGA-GBM databases. Tumor sphere formation assays and limiting dilution assays were applied to assess the implications of ARPC1B in tumorigenesis. Apoptosis, comet, γ-H2AX immunofluorescence (IF), and cell cycle distribution assays were used to evaluate the effect of ARPC1B on radiotherapy resistance. Immunoprecipitation (IP) and mass spectrometry analysis were used to detect ARPC1B-interacting proteins. Immune blot assays were performed to evaluate protein ubiquitination, and deletion mutant constructs were designed to determine the binding sites of protein interactions. The Spearman correlation algorithm was performed to screen for drugs that indicated cell sensitivity by the expression of ARPC1B. An intracranial xenograft GSC mouse model was used to investigate the role of ARPC1B in vivo. Results We concluded that ARPC1B was significantly upregulated in MES-GBM/GSCs and was correlated with a poor prognosis. Both in vitro and in vivo assays indicated that knockdown of ARPC1B in MES-GSCs reduced tumorigenicity and resistance to IR treatment, whereas overexpression of ARPC1B in PN-GSCs exhibited the opposite effects. Mechanistically, ARPC1B interacted with IFI16 and HuR to maintain protein stability. In detail, the Pyrin of IFI16 and RRM2 of HuR were implicated in binding to ARPC1B, which counteracted TRIM21-mediated degradation of ubiquitination to IFI16 and HuR. Additionally, the function of ARPC1B was dependent on IFI16-induced activation of NF-κB pathway and HuR-induced activation of STAT3 pathway. Finally, we screened AZD6738, an ataxia telangiectasia mutated and rad3-related (ATR) inhibitor, based on the expression of ARPC1B. In addition to ARPC1B expression reflecting cellular sensitivity to AZD6738, the combination of AZD6738 and radiotherapy exhibited potent antitumor effects both in vitro and in vivo. Conclusion ARPC1B promoted MES phenotype maintenance and radiotherapy resistance by inhibiting TRIM21-mediated degradation of IFI16 and HuR, thereby activating the NF-κB and STAT3 signaling pathways, respectively. AZD6738, identified based on ARPC1B expression, exhibited excellent anti-GSC activity in combination with radiotherapy.

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“…Upregulated MALAT1 activated transcriptional factor NF-kB. Interestingly, the RNA-binding protein HuR, which is reported to have antiapoptotic activity [ 75 , 76 ], is essential for MALAT1 modification and MALAT1-mediated NF-kB activation. Moreover, it plays an important role in m6A methylation of SOX2 mRNA, leading to its activation [ 77 ].…”

Section: Non-coding Rna and Apoptosismentioning

confidence: 99%

Post-Transcriptional Modifications of RNA as Regulators of Apoptosis in Glioblastoma

Dome

Дымова

Richter

et al. 2022

IJMS

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This review is devoted to changes in the post-transcriptional maturation of RNA in human glioblastoma cells, which leads to disruption of the normal course of apoptosis in them. The review thoroughly highlights the latest information on both post-transcriptional modifications of certain regulatory RNAs, associated with the process of apoptosis, presents data on the features of apoptosis in glioblastoma cells, and shows the relationship between regulatory RNAs and the apoptosis in tumor cells. In conclusion, potential target candidates are presented that are necessary for the development of new drugs for the treatment of glioblastoma.

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The versatile role of HuR in Glioblastoma and its potential as a therapeutic target for a multi-pronged attack

Cited by 15 publications

References 178 publications

A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5

A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5

ARPC1B promotes mesenchymal phenotype maintenance and radiotherapy resistance by blocking TRIM21-mediated degradation of IFI16 and HuR in glioma stem cells

Post-Transcriptional Modifications of RNA as Regulators of Apoptosis in Glioblastoma

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