The human box C/D snoRNAs U3 and U8 are required for pre-rRNA processing and tumorigenesis
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Jean-Louis Langhendries1, Emilien Nicolas1, Gilles Doumont3, Serge Goldman2,3, Denis L.J. Lafontaine1,3
1RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S.-FNRS), Université Libre de Bruxelles (ULB), BioPark Campus, Gosselies, Belgium
2Nuclear Medecine, Erasme Hospital, Université Libre de Bruxelles, Belgium
3Center for Microscopy and Molecular Imaging (CMMI), BioPark campus, Université Libre de Bruxelles, Belgium
Denis L.J. Lafontaine, email: email@example.com
Keywords: snoRNA, nucleolus, ribosome, tumorigenesis, cancer
Received: April 11, 2016 Accepted: June 30, 2016 Published: August 09, 2016
Small nucleolar RNAs (snoRNAs) are emerging as a novel class of proto-oncogenes and tumor suppressors; their involvement in tumorigenesis remains unclear. The box C/D snoRNAs U3 and U8 are upregulated in breast cancers. Here we characterize the function of human U3 and U8 in ribosome biogenesis, nucleolar structure, and tumorigenesis. We show in breast (MCF-7) and lung (H1944) cancer cells that U3 and U8 are required for pre-rRNA processing reactions leading, respectively, to synthesis of the small and large ribosomal subunits. U3 or U8 depletion triggers a remarkably potent p53-dependent anti-tumor stress response involving the ribosomal proteins uL5 (RPL11) and uL18 (RPL5). Interestingly, the nucleolar structure is more sensitive to perturbations in lung cancer than in breast cancer cells. We reveal in a mouse xenograft model that the tumorigenic potential of cancer cells is reduced in the case of U3 suppression and totally abolished upon U8 depletion. Tumors derived from U3-knockdown cells displayed markedly lower metabolic volume and activity than tumors derived from aggressive control cancer cells. Unexpectedly, metabolic tracer uptake by U3-suppressed tumors appeared more heterogeneous, indicating distinctive tumor growth properties that may reflect non-conventional regulatory functions of U3 (or fragments derived from it) in mRNA metabolism.
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