HuR is a post-transcriptional regulator of core metabolic enzymes in pancreatic cancer

Abstract

Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNA-binding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein-immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment.

Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

“…2C), a transcript that is known to be stabilized during iron deprivation (32). DFO treatment also led to an increase in the stability of Hk2 and Slc2a1, which encode proteins involved in glucose metabolism, and whose expression can be influenced post-transcriptionally during nutrient stress via RNA-binding factors (33)(34)(35). Importantly, the half-lives of OxPhos transcripts determined from our analyses were similar to those from a global analysis of transcript turnover (36).…”

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

“…Disparity in HuR expression and localization is likely to be heavily influenced by the tumor microenvironment, which can show significant interand intratumoral heterogeneity in terms of blood flow, oxygenation, and nutrient supply (47). We have shown that HuR is engaged under conditions of hypoglycemia and hypoxia (33). As such, HuR expression and cytoplasmic localization are expected to be high in regions within ovarian tumors with the least amount of vascularization (i.e., greatest hypoxia and hypoglycemia).…”

“…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.…”

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

“…In this regard, the cytoplasmic translocation of HuR has been reported in response to other stress conditions, including DNA damage and glucose deprivation. 49,50 Given our findings, modulating HuR levels or activity may constitute a rational pharmacological approach to manipulate VEGFA in disorders where it is desirable to inhibit neovascularization, such as diabetic retinopathy and cancer.…”