The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance

Abstract

Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by shRNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Since bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV crosslinking and RNA immunoprecipitation, we show that HuR bound to the 3' untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target.

Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA

“…BCL2 mRNA bears an AU-rich 3′ UTR and was reported to be a target of an RNA-binding protein, ELAV-like protein 1 (HuR). 25,26 Consistent with this report, HuR bound to BCL2 3′ UTR-4 ( Figure 2b). We further divided 3′ UTR-1 into four overlapping fragments (3′ UTR-A, -B, -C, and -D) and found that Tra2β predominantly bound to the region within 3′ UTR-B (nt 1294-1541; Figure 2c Figure 2e, the rate of decay for BCL2 mRNA in Tra2β siRNA-treated cells in the presence of actinomycin D (t 1/2 = 2.1 ± 0.3 h) was faster than that of control siRNA-treated cells (t 1/2 = 7.5 ± 0.6 h).…”

Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth

“…Our previous studies in preclinical pancreatic cancer models (33)(34)(35)(36)(37)(38), as well as studies by others (17,19,20,24,(39)(40)(41), provided the rationale for investigating HuR inhibition in ovarian tumors We first established that suppression of HuR expression reduces proliferation, anchorage-independent growth, and invasion of ovarian cancer cells in vitro. We further demonstrate HuR inhibitionmediated reduction in tumor growth rate, delay in ascites development, and extension of lifespan by nearly 1.5-fold in two different ovarian cancer mouse models, a xenograft model and an orthotopic model in which mice bear tumors throughout the peritoneum.…”

“…The role of HuR in posttranscriptional regulation of multiple genes that promote survival of ovarian tumor cells provides an opportunity to develop an alternative strategy that targets multiple core signaling pathways at once. Indeed, proof-of-concept studies using HuR knockout mice and intracranial injection of mice with genetically silenced HuR primary glioblastoma cells have shown a reduction in colon tumor and glioblastoma growth, respectively (19,20). One approach to inhibit HuR is through targeted delivery of functional siRNA.…”

Neuroprotection requires the functions of the RNA-binding protein HuR

“…Previous reports established the neuroprotective effect of Bcl-2 in neurons. [61][62][63] HuR has also been linked to the activation of prosurvival Bcl-2 family members 56,64,65 through the regulation of their turnover and translation, 56,[66][67][68] In HT-22 cells, HuR maintains Bcl2 mRNA stability and translation at a constant rate to buffer its requirement during assault and preserve mitochondrial homeostasis.…”