Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2

Abstract

Esophageal cancer-related gene 2 (ECRG2) is a newer tumor suppressor whose function in the regulation of cell growth and apoptosis remains to be elucidated. Here we show that ECRG2 expression was upregulated in response to DNA damage, and increased ECRG2 expression induced growth suppression in cancer cells but not in non-cancerous epithelial cells. ECRG2-mediated growth suppression was associated with activation of caspases and marked reduction in the levels of apoptosis inhibitor, X chromosome-linked inhibitor of apoptosis protein (XIAP). ECRG2, via RNA-binding protein human antigen R (HuR), regulated XIAP mRNA stability and expression. Furthermore, ECRG2 increased HuR ubiquitination and degradation but was unable to modulate the non-ubiquitinable mutant form of HuR. We also identified missense and frame-shift ECRG2 mutations in various human malignancies and noted that, unlike wild-type ECRG2, one cancer-derived ECRG2 mutant harboring glutamic acid instead of valine at position 30 (V30E) failed to induce cell death and activation of caspases. This naturally occurring V30E mutant also did not suppress XIAP and HuR. Importantly, the V30E mutant overexpressing cancer cells acquired resistance against multiple anticancer drugs, thus suggesting that ECRG2 mutations appear to have an important role in the acquisition of anticancer drug resistance in a subset of human malignancies.

Posttranslational control of HuR function

“…In HeLa cells, HuR was found to be ubiquitinated and degraded upon heat shock, but phosphorylation by CHK2 enhanced resistance of HuR against proteasomal degradation . Recently, the tumor suppressor esophageal cancer‐related gene 2 (ECRG2) was shown to increase in response to DNA damage, in turn favoring ubiquitination of HuR at K182 and HuR degradation . In the same report, lowering HuR led to reduced expression of the inhibitor of apoptosis XIAP (encoded by the HuR target XIAP mRNA), prompting the authors to propose that the tumor suppressive actions of ECRG2 were associated with the suppression of HuR and XIAP levels .…”

“…Recently, the tumor suppressor esophageal cancer‐related gene 2 (ECRG2) was shown to increase in response to DNA damage, in turn favoring ubiquitination of HuR at K182 and HuR degradation . In the same report, lowering HuR led to reduced expression of the inhibitor of apoptosis XIAP (encoded by the HuR target XIAP mRNA), prompting the authors to propose that the tumor suppressive actions of ECRG2 were associated with the suppression of HuR and XIAP levels . Glycolytic stress in prostate cancer cells triggered the translocation of HuR to the cytoplasm, where it was targeted by the ubiquitin E3 ligase βTrCP1 for degradation .…”

Long Noncoding RNAs and RNA‐Binding Proteins in Oxidative Stress, Cellular Senescence, and Age‐Related Diseases

“…HuR is also implicated in DDR by directly regulating RNA metabolism of p53, WEE1, and non-POU domain-containing octamer-binding protein (NONO, also known as p54NRB) [ 117 , 118 ]. Esophageal cancer-related gene 2 (ECRG2), a DNA damage-inducible tumor suppressor, can regulate XIAP-mediated cell death by downregulating HuR expression [ 119 ].…”

α4 Coordinates Small Intestinal Epithelium Homeostasis by Regulating Stability of HuR

“…These findings demonstrate the importance of reduced levels of HuR in the pathogenesis of gut barrier dysfunction in IE-␣4 Ϫ/Ϫ mice. However, HuR in the intestinal epithelium modulates distinct pathways of cell proliferation, migration, differentiation, and apoptosis (20)(21)(22)(37)(38)(39); HuR deletion also reduces tumor development by targeting multiple genes (35). The exact mechanisms whereby decreased HuR levels following ␣4 deletion delay mucosal maturation, as evidenced by crypt hyperplasia and villus shrinkage, defective differentiation of Paneth cells, and reduced migration, remain unknown and are being intensely investigated in our laboratory.…”

“…HuR is phosphorylated by IKK␣ at S304, leading to HuR binding to the E3 ubiquitin ligase ␤-transducin repeat-containing protein for its degradation in response to metabolic stress (29), whereas HuR phosphorylation by checkpoint kinase 2 (CHEK2) enhances the resistance of HuR to proteasomal degradation (28). Recently, the tumor suppressor ECRG2 was shown to reduce cellular HuR levels by favoring ubiquitination of HuR at K182 for its degradation (39). Our results indicate that inhibition of either IKK␣ activity by BAY11-7082 or the proteasome by MG132 restored HuR levels in ␣4-silenced cells.…”