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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2018

Open Access 01-12-2018 | Research

The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models

Authors: Carmen Vicente, Rocco Stirparo, Sofie Demeyer, Charles E. de Bock, Olga Gielen, Mardelle Atkins, Jiekun Yan, Georg Halder, Bassem A. Hassan, Jan Cools

Published in: Journal of Hematology & Oncology | Issue 1/2018

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Abstract

Background

The CNOT3 protein is a subunit of the CCR4-NOT complex, which is involved in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL).

Methods

Here, we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, and other members of the CCR4-NOT complex.

Results

Our data show that knockdown of Not3, the structural components Not1/Not2, and the deadenylases twin/Pop2 all result in increased tumor formation. In addition, overexpression of Not3 could reduce tumor formation. Not3 downregulation has a mild but broad effect on gene expression and leads to increased levels of genes involved in DNA replication and ribosome biogenesis. CycB upregulation also contributes to the Not3 tumor phenotype. Similar findings were obtained in human T-ALL cell lines, pointing out the conserved function of Not3.

Conclusions

Together, our data establish a critical role for Not3 and the entire CCR4-NOT complex as tumor suppressor.
Appendix
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Literature
1.
2.
Shirai Y-T, Suzuki T, Morita M, Takahashi A, Yamamoto T. Multifunctional roles of the mammalian CCR4-NOT complex in physiological phenomena. Front Genet. 2014;5:286.CrossRefPubMedPubMedCentral
3.
Wahle E, Winkler GS. RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes. Biochim Biophys Acta. 1829;2013:561–70.
4.
Ito K, Inoue T, Yokoyama K, Morita M, Suzuki T, Yamamoto T. CNOT2 depletion disrupts and inhibits the CCR4-NOT deadenylase complex and induces apoptotic cell death. Genes Cells. 2011;16:368–79.CrossRefPubMed
5.
Ito K, Takahashi A, Morita M, Suzuki T, Yamamoto T. The role of the CNOT1 subunit of the CCR4-NOT complex in mRNA deadenylation and cell viability. Protein Cell. 2011;2:755–63.CrossRefPubMedPubMedCentral
6.
Morita M, Oike Y, Nagashima T, Kadomatsu T, Tabata M, Suzuki T, et al. Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3+/− mice. EMBO J. 2011;30:4678–91.CrossRefPubMedPubMedCentral
7.
Watanabe C, Morita M, Hayata T, Nakamoto T, Kikuguchi C, Li X, et al. Stability of mRNA influences osteoporotic bone mass via CNOT3. Proc Natl Acad Sci U S A. 2014;111:2692–7.CrossRefPubMedPubMedCentral
8.
Inoue T, Morita M, Hijikata A, Fukuda-Yuzawa Y, Adachi S, Isono K, et al. CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability. J Exp Med. 2015;212:1465–79.CrossRefPubMedPubMedCentral
9.
Mayr C, Bartel DP. Widespread shortening of 3’UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell. 2009;138:673–84.CrossRefPubMedPubMedCentral
10.
Wiestner A, Tehrani M, Chiorazzi M, Wright G, Gibellini F, Nakayama K, et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood. 2007;109:4599–606.CrossRefPubMedPubMedCentral
11.
Rounbehler RJ, Fallahi M, Yang C, Steeves MA, Li W, Doherty JR, et al. Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state. Cell. 2012;150:563–74.CrossRefPubMedPubMedCentral
12.
Hodson DJ, Janas ML, Galloway A, Bell SE, Andrews S, Li CM, et al. Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia. Nat Immunol. 2010;11:717–24.CrossRefPubMedPubMedCentral
13.
De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, Girardi T, et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat Genet. 2013;45:186–90.CrossRefPubMed
14.
Vicente C, Schwab C, Broux M, Geerdens E, Degryse S, Demeyer S, et al. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica. 2015;100:1301–10.CrossRefPubMedPubMedCentral
15.
Seki M, Kimura S, Isobe T, Yoshida K, Ueno H, Nakajima-Takagi Y, et al. Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. Nat Genet. 2017;49:1274–81.CrossRefPubMed
16.
Liu Z, Hornakova T, Hornakova T, Li F, Staerk J, Staerk J, et al. Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers. J Biol Chem. 2009;284:6773–81.CrossRef
17.
La Starza R, Barba G, Demeyer S, Pierini V, Di Giacomo D, Gianfelici V, et al. Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia. Haematologica. 2016;101:951–8.CrossRefPubMedPubMedCentral
18.
Bossuyt W, De Geest N, Aerts S, Leenaerts I, Marynen P, Hassan BA. The atonal proneural transcription factor links differentiation and tumor formation in Drosophila. PLoS Biol. 2009;7:e40.PubMed
19.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.CrossRefPubMedPubMedCentral
20.
Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.CrossRefPubMed
21.
22.
Lyne R, Smith R, Rutherford K, Wakeling M, Varley A, Guillier F, et al. FlyMine: an integrated database for Drosophila and Anopheles genomics. Genome Biol. 2007;8:R129.CrossRefPubMedPubMedCentral
23.
Dagklis A, Pauwels D, Lahortiga I, Geerdens E, Bittoun E, Cauwelier B, et al. Hedgehog pathway mutations in T-cell acute lymphoblastic leukemia. Haematologica. 2015;100:e102–5.CrossRefPubMedPubMedCentral
24.
Jiao X, Sherman BT, Huang DW, Stephens R, Baseler MW, Lane HC, et al. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 2012;28:1805–6.CrossRefPubMedPubMedCentral
25.
Ferres-Marco D, Gutierrez-Garcia I, Vallejo DM, Bolivar J, Gutierrez-Aviño FJ, Dominguez M. Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature. 2006;439:430–6.CrossRefPubMed
26.
Neely GG, Kuba K, Cammarato A, Isobe K, Amann S, Zhang L, et al. A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function. Cell. 2010;141:142–53.CrossRefPubMedPubMedCentral
27.
Basquin J, Roudko VV, Rode M, Basquin C, Séraphin B, Conti E. Architecture of the nuclease module of the yeast Ccr4-not complex: the Not1-Caf1-Ccr4 interaction. Mol Cell. 2012;48:207–18.CrossRefPubMed
28.
Petit A-P, Wohlbold L, Bawankar P, Huntzinger E, Schmidt S, Izaurralde E, et al. The structural basis for the interaction between the CAF1 nuclease and the NOT1 scaffold of the human CCR4-NOT deadenylase complex. Nucleic Acids Res. 2012;40:11058–72.CrossRefPubMedPubMedCentral
29.
Hu G, Kim J, Xu Q, Leng Y, Orkin SH, Elledge SJ. A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. Genes Dev. 2009;23(7):837–48.CrossRefPubMedPubMedCentral
30.
Bach EA, Ekas LA, Ayala-Camargo A, Flaherty MS, Lee H, Perrimon N, et al. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene Expr Patterns. 2007;7:323–31.CrossRefPubMed
31.
Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–24.CrossRefPubMed
32.
Faraji F, Hu Y, Wu G, Goldberger NE, Walker RC, Zhang J, et al. An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease. Genome Res. 2014;24:227–40.CrossRefPubMedPubMedCentral
33.
Cejas P, Cavazza A, Yandava CN, Moreno V, Horst D, Moreno-Rubio J, et al. Transcriptional regulator CNOT3 defines an aggressive colorectal cancer subtype. Cancer Res. 2017;77:766–79.CrossRefPubMed
34.
Richter-Pechańska P, Kunz JB, Hof J, Zimmermann M, Rausch T, Bandapalli OR, et al. Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia. Blood Cancer J. 2017;7:e523.CrossRefPubMedPubMedCentral
35.
Suzuki T, Kikuguchi C, Sharma S, Sasaki T, Tokumasu M, Adachi S, et al. CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins. Sci Rep. 2015;5:14779.CrossRefPubMedPubMedCentral
36.
Song Y, Zhao C, Dong L, Fu M, Xue L, Huang Z, et al. Overexpression of cyclin B1 in human esophageal squamous cell carcinoma cells induces tumor cell invasive growth and metastasis. Carcinogenesis. 2008;29:307–15.CrossRefPubMed
37.
Yuan J, Yan R, Krämer A, Eckerdt F, Roller M, Kaufmann M, et al. Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene. 2004;23:5843–52.CrossRefPubMed
38.
Kauffmann A, Rosselli F, Lazar V, Winnepenninckx V, Mansuet-Lupo A, Dessen P, et al. High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene. 2008;27:565–73.CrossRefPubMed
39.
40.
Boon K, Caron HN, van Asperen R, Valentijn L, Hermus MC, van Sluis P, et al. N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis. EMBO J. 2001;20:1383–93.CrossRefPubMedPubMedCentral
41.
Shenoy N, Kessel R, Bhagat TD, Bhattacharyya S, Yu Y, McMahon C, et al. Alterations in the ribosomal machinery in cancer and hematologic disorders. J Hematol Oncol. 2012;5:32.CrossRefPubMedPubMedCentral
42.
Kim J-H, You K-R, Kim IH, Cho B-H, Kim C-Y, Kim D-G. Over-expression of the ribosomal protein L36a gene is associated with cellular proliferation in hepatocellular carcinoma. Hepatology. 2004;39:129–38.CrossRefPubMed
Metadata
Title
The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models
Authors
Carmen Vicente
Rocco Stirparo
Sofie Demeyer
Charles E. de Bock
Olga Gielen
Mardelle Atkins
Jiekun Yan
Georg Halder
Bassem A. Hassan
Jan Cools
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2018
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-018-0650-0

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