MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin
| Autor: | Georg von Jonquieres, Murray D. Norris, Giovanni Perini, Sieu L. Tran, Jamie I. Fletcher, Rosemary O'Brien, Wendy B. London, Michelle Haber, Hilda A. Pickett, Chen Yang, Cheng Fei Kong, Michelle F. Maritz, Jayne Murray, Claudia Flemming, Karen L. MacKenzie, Amanda J. Russell, Stefania Purgato, Bing Liu, Preethi H. Gunaratne |
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| Přispěvatelé: | O'Brien, R, Tran, SL, Maritz, MF, Liu, B, Kong, CF, Purgato, S, Yang, C, Murray, J, Russell, AJ, Flemming, CL, Von Jonquieres, G, Pickett, HA, London, WB, Haber, M, Gunaratne, PH, Norris, MD, Perini, G, Fletcher, JI, MacKenzie, KL, O'Brien, Rosemary, Tran, Sieu L., Maritz, Michelle F., Liu, Bing, Kong, Cheng Fei, Purgato, Stefania, Yang, Chen, Murray, Jayne, Russell, Amanda J., Flemming, Claudia L., Von Jonquieres, Georg, Pickett, Hilda A., London, Wendy B., Haber, Michelle, Gunaratne, Preethi H., Norris, Murray D., Perini, Giovanni, Fletcher, Jamie I., Mackenzie, Karen L |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Telomerase Cancer Research Ribosome biogenesis Cell Cycle Proteins Biology Dyskerin Proto-Oncogene Proteins c-myc 03 medical and health sciences Telomerase RNA component Neuroblastoma 0302 clinical medicine Downregulation and upregulation Ribosomal protein medicine Humans functions and broader implications RNA-binding protein dyskerin Cells Cultured RNA Nuclear Proteins medicine.disease G1 Phase Cell Cycle Checkpoints 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Tumor Suppressor Protein p53 DKC1 gene Ribosomes |
| Zdroj: | Cancer research. 76(12) |
| ISSN: | 1538-7445 |
| Popis: | The RNA-binding protein dyskerin, encoded by the DKC1 gene, functions as a core component of the telomerase holoenzyme as well as ribonuclear protein complexes involved in RNA processing and ribosome biogenesis. The diverse roles of dyskerin across many facets of RNA biology implicate its potential contribution to malignancy. In this study, we examined the expression and function of dyskerin in neuroblastoma. We show that DKC1 mRNA levels were elevated relative to normal cells across a panel of 15 neuroblastoma cell lines, where both N-Myc and c-Myc directly targeted the DKC1 promoter. Upregulation of MYCN was shown to dramatically increase DKC1 expression. In two independent neuroblastoma patient cohorts, high DKC1 expression correlated strongly with poor event-free and overall survival (P < 0.0001), independently of established prognostic factors. RNAi-mediated depletion of dyskerin inhibited neuroblastoma cell proliferation, including cells immortalized via the telomerase-independent ALT mechanism. Furthermore, dyskerin attenuation impaired anchorage-independent proliferation and tumor growth. Overexpression of the telomerase RNA component, hTR, demonstrated that this proliferative impairment was not a consequence of telomerase suppression. Instead, ribosomal stress, evidenced by depletion of small nucleolar RNAs and nuclear dispersal of ribosomal proteins, was the likely cause of the proliferative impairment in dyskerin-depleted cells. Accordingly, dyskerin suppression caused p53-dependent G1 cell-cycle arrest in p53 wild-type cells, and a p53-independent pathway impaired proliferation in cells with p53 dysfunction. Together, our findings highlight dyskerin as a new therapeutic target in neuroblastoma with crucial telomerase-independent functions and broader implications for the spectrum of malignancies driven by MYC family oncogenes. Cancer Res; 76(12); 3604–17. ©2016 AACR. |
| Databáze: | OpenAIRE |
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