Abstract
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.
Highlights
Ribosomes are cellular nanomachines essential for protein production in all living cells
We have focused on two conserved snoRNAs, the box C/D snoRNAs U3 and U8, whose functions in pre-ribosomal RNA (rRNA) processing have been characterized in various eukaryotic models, but surprisingly never in humans
Our data obtained with breast, cervix, colon, and lung cancer cells demonstrate that U3 and U8 are required, respectively, for early and late pre-rRNA processing steps (Figures 1 and 2)
Summary
Ribosomes are cellular nanomachines essential for protein production in all living cells. In addition to being extensively processed, i.e. undergoing multiple cleavages that yield the mature rRNAs (Figure S1 and [2, 3]), precursor rRNAs (pre-rRNAs) are heavily modified post-transcriptionally [4] This can involve isomerization of specific nucleobases (conversion of uridines to pseudouridines) or addition of particular chemical groups to specific nucleotides (i.e. acetylation, aminocarboxylpropylation, and methylation, see [5]). The RNase MRP is involved in processing nucleolar pre-rRNAs [8], a function that surprisingly might not have been conserved in human cells [9] This observation highlights the need to explore in detail the functions of snoRNAs in different organisms, even in cases of structural conservation, to avoid fallacious extrapolations
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