Ribosome biogenesis: Achilles heel of cancer?

Sluis, Marjolein van; McStay, Brian

doi:10.18632/genesandcancer.14

Cited by 22 publications

(16 citation statements)

References 11 publications

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“…They do, however, exhibit stronger correlations with ZFAS1 in normal tissue compared to breast cancer tissue. This may be a reflection of deregulated ribosome function and synthesis that occurs in neoplastic cells [28]. Interestingly, the respective ribosomal proteins have been found to participate in ribosome synthesis as regulators of ribosomal structure [29, 32, 33] and in formation of mature rRNA [30, 31].…”

Section: Discussionmentioning

confidence: 99%

ZFAS1: a long noncoding RNA associated with ribosomes in breast cancer cells

et al. 2016

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BackgroundMost of the eukaryotic genome is transcribed, yielding a complex network of transcripts including thousands of lncRNAs that generally lack protein coding potential. However, only a small percentage of these molecules has been functionally characterised, and discoveries of specific functions demonstrate layers of complexity. A large percentage of lncRNAs is located in the cytoplasm, associated with ribosomes but the function of the majority of these transcripts is unclear. The current study analyses putative mechanisms of action of the lncRNA species member ZFAS1 that was initially discovered by microarray analysis of murine tissues undergoing mammary gland development. As developmental genes are often deregulated in cancer, here we have studied its function in breast cancer cell lines.ResultsUsing human breast cancer cell lines, ZFAS1 was found to be expressed in all cell lines tested, albeit at different levels of abundance. Following subcellular fractionation, human ZFAS1 was found in both nucleus and cytoplasm (as is the mouse orthologue) in an isoform-independent manner. Sucrose gradients based on velocity sedimentation were utilised to separate the different components of total cell lysate, and surprisingly ZFAS1 was primarily co-localised with light polysomes. Further investigation into ribosome association through subunit dissociation studies showed that ZFAS1 was predominantly associated with the 40S small ribosomal subunit. The expression levels of ZFAS1 and of mRNAs encoding several ribosomal proteins that have roles in ribosome assembly, production and maturation were tightly correlated. ZFAS1 knockdown significantly reduced RPS6 phosphorylation.ConclusionA large number of lncRNAs associate with ribosomes but the function of the majority of these lncRNAs has not been elucidated. The association of the lncRNA ZFAS1 with a subpopulation of ribosomes and the correlation with expression of mRNAs for ribosomal proteins suggest a ribosome-interacting mechanism pertaining to their assembly or biosynthetic activity. ZFAS1 may represent a new class of lncRNAs which associates with ribosomes to regulate their function.ReviewersThis article was reviewed by Christine Vande Velde, Nicola Aceto and Haruhiko Siomi.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0165-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

ZFAS1: a long noncoding RNA associated with ribosomes in breast cancer cells

et al. 2016

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“…The structural characterization of such an interaction and the consequences of its disruption provide a good outset for the study of the effects of directed ribosome biogenesis impairment. It is of special interest to emphasize that rapid proliferation depends on high rates of ribosome production ( 52 ). In this context the PeBoW complex is required for cell proliferation ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

The structure of Erb1-Ytm1 complex reveals the functional importance of a high-affinity binding between two β-propellers during the assembly of large ribosomal subunits in eukaryotes

et al. 2015

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Ribosome biogenesis is one of the most essential pathways in eukaryotes although it is still not fully characterized. Given the importance of this process in proliferating cells, it is obvious that understanding the macromolecular details of the interactions that take place between the assembly factors, ribosomal proteins and nascent pre-rRNAs is essentially required for the development of new non-genotoxic treatments for cancer. Herein, we have studied the association between the WD40-repeat domains of Erb1 and Ytm1 proteins. These are essential factors for the biogenesis of 60S ribosomal subunits in eukaryotes that form a heterotrimeric complex together with the also essential Nop7 protein. We provide the crystal structure of a dimer formed by the C-terminal part of Erb1 and Ytm1 from Chaetomium thermophilum at 2.1 Å resolution. Using a multidisciplinary approach we show that the β-propeller domains of these proteins interact in a novel manner that leads to a high-affinity binding. We prove that a point mutation within the interface of the complex impairs the interaction between the two proteins and negatively affects growth and ribosome production in yeast. Our study suggests insights into the association of the Erb1-Ytm1 dimer with pre-ribosomal particles.

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“…We found that although TSR1 has not been strongly associated with PCa previously, it has been suggested to play a putative role in the quality control of 18S rRNA precursor production (Tafforeau et al , 2013). Taking this alongside the importance of ribosome biogenesis in cancer (van Sluis and McStay, 2014), it is perhaps unsurprising that a molecule involved in this process has implicated in PCa. In addition, work on tissue has shown TSR1 RNA expression in prostate tissue, although its highest levels of expression are found in the testis (Ardlie et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study

et al. 2016

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Background:Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease.Methods:We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa.Results:We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an ‘interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6.Conclusions:Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.

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Ribosome biogenesis: Achilles heel of cancer?

Cited by 22 publications

References 11 publications

ZFAS1: a long noncoding RNA associated with ribosomes in breast cancer cells

ZFAS1: a long noncoding RNA associated with ribosomes in breast cancer cells

The structure of Erb1-Ytm1 complex reveals the functional importance of a high-affinity binding between two β-propellers during the assembly of large ribosomal subunits in eukaryotes

Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study

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