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Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Oncogene volume 28, pages 1904–1915 (2009)Cite this article

Abstract

The cytoplasmic level of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is significantly correlated with the elevated expression of thymidine phosphorylase (TP), and high levels of both proteins are predictive of a poor prognosis in nasopharyngeal carcinoma (NPC). We herein show that TP is highly induced by serum deprivation in NPC cells, and that this is due to an increase in the half-life of the TP mRNA, as shown by nuclear run-on and actinomycin D assays. We further show that the CU-rich element of the TP mRNA directly interacts with hnRNP K, as demonstrated by immunoprecipitation RT–PCR assays, and the nucleus-to-cytoplasm translocation of hnRNP K. Blockade of hnRNP K expression reduces TP expression, suggesting that hnRNP K acts in the upregulation of TP. Mechanistically, both MEK inhibitor and the hnRNP K ERK-phosphoacceptor-site mutant decrease cytoplasmic accumulation of hnRNP K, suggesting that ERK-dependent phosphorylation is critical for TP induction. Furthermore, we found that hnRNP K-mediated TP induction allows NPC cells to resist hypoxia-induced apoptosis. Our results collectively establish the regulation and role of ERK-mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.

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Acknowledgements

Grant support was provided by the Ministry of Education, Taiwan (to Chang Gung University), the National Science Council, Taiwan (grants NSC 94-2314-B-182A-188, 94-3112-B-182-005 and 95-2320-B-182-001 to Y-S Chang) and Chang Gung Memorial Hospital, Taiwan (grants CMRPD150961 and CMRPG360221 to Y-S Chang). Special thanks to Chung Shan Medical University for supporting CL Liang to attend the 12th International EBV Symposium.

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Authors and Affiliations

  1. Chang Gung Molecular Medicine Research Center, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan

    L-C Chen, H-P Liu, C Hsueh, J-S Yu & Y-S Chang

  2. Graduate Institute of Basic Medical Sciences, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan

    H-P Li, J-S Yu & Y-S Chang

  3. Department of Pathology, Chang Gung Memorial Hospital at Lin-Kou, Kwei-Shan, Taoyuan, Taiwan

    C Hsueh

  4. Department of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan

    C-L Liang

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  1. L-C Chen
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Correspondence to Y-S Chang.

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Chen, LC., Liu, HP., Li, HP. et al. Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells. Oncogene 28, 1904–1915 (2009). https://doi.org/10.1038/onc.2009.55

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