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

Oncogene volume 35, pages 2565–2573 (2016)Cite this article

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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.

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Acknowledgements

We thank Dr Myriam Gorospe (NIH/NIA) for kindly providing the pTAP-HuR and pTAP-HuR-K182R as well as Ad-GFP and Ad-HuR expression vectors and Dr Bert Vogelstein’s laboratory (Johns Hopkins University School of Medicine, Baltimore, MD, USA) for kindly providing the RKO p53−/− cell line. These studies are supported in part by the Carol M Baldwin Breast Cancer Research Fund to Dr Ying Huang.

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  1. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, USA

    C Lucchesi, M S Sheikh & Y Huang

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  1. C Lucchesi
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Correspondence to Y Huang.

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Lucchesi, C., Sheikh, M. & Huang, Y. Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2. Oncogene 35, 2565–2573 (2016). https://doi.org/10.1038/onc.2015.339

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