Hu antigen R (HuR) multimerization contributes to glioma disease progression

Abstract

Among primary brain cancers, gliomas are the most deadly and most refractory to current treatment modalities. Previous reports overwhelmingly support the role of the RNA-binding protein Hu antigen R (HuR) as a positive regulator of glioma disease progression. HuR expression is consistently elevated in tumor tissues, and a cytoplasmic localization appears essential for HuR-dependent oncogenic transformation. Here, we report HuR aggregation (multimerization) in glioma and the analysis of this tumor-specific HuR protein multimerization in clinical brain tumor samples. Using a split luciferase assay, a bioluminescence resonance energy transfer technique, and site-directed mutagenesis, we examined the domains involved in HuR multimerization. Results obtained with the combination of the split HuR luciferase assay with the bioluminescence resonance energy transfer technique suggested that multiple (at least three) HuR molecules come together during HuR multimerization in glioma cells. Using these data, we developed a model of HuR multimerization in glioma cells. We also demonstrate that exposing glioma cells to the HuR inhibitor tanshinone group compound 15,16-dihydrotanshinone-I or to the newly identified compound 5 disrupts HuR multimerization modules and reduces tumor cell survival and proliferation. In summary, our findings provide new insights into HuR multimerization in glioma and highlight possible pharmacological approaches for targeting HuR domains involved in cancer cell-specific multimerization.

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer

“…Previous studies showed that HuR promotes proliferation in cancer cells (20,38), including wild-type gliomas (39,40). Here, we investigated the effect of HuR expression on cell proliferation in cancer cells that harbor a natural heterozygous IDH1 mutation.…”

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

“…Previously, we reported on the vital role of HuR in GB where it is highly upregulated in tumor cells and promotes tumor progression in vivo (Filippova et al, ; Filippova et al, ; Nabors et al, ; Nabors, Gillespie, Harkins, & King, ). Blocking HuR either by chemical inhibition or shRNA‐mediated silencing can produce a potent anti‐glioma effect (Filippova et al, ; Filippova et al, ; Wang, Hjelmeland, Nabors, & King, ). In the current study, we hypothesized that HuR expression in TAMs promotes tumor progression through its role in modulating the expression of key cytokines and chemokines.…”

“…HuR can also bind to the 5 0 UTR, often at or near internal ribosome entry sites, and either inhibits or augments translation (Galban et al, 2008;Kullmann, Gopfert, Siewe, & Hengst, 2002;Meng et al, 2005). Previously, we reported on the vital role of HuR in GB where it is highly upregulated in tumor cells and promotes tumor progression in vivo (Filippova et al, 2011;Filippova et al, 2017;Nabors et al, 2003;Nabors, Gillespie, Harkins, & King, 2001). Blocking HuR either by chemical inhibition or shRNA-mediated silencing can produce a potent anti-glioma effect (Filippova et al, 2011;Filippova et al, 2017;Wang, Hjelmeland, Nabors, & King, 2019).…”

RNA-Targeted Therapies and High-Throughput Screening Methods

“…DHTS showed effects similar to MS-444 in glioma, by inhibiting HuR multimerisation and decreasing cellular HuR protein level. Importantly, DHTS showed dose-dependent cytotoxicity towards glioma cells [140]. Based on the structure of DHTS, a series of tanshinone mimics were synthesised.…”