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Aurora B expression and histone variant H1.4S27 phosphorylation are no longer coordinated during metaphase in aneuploid colorectal carcinomas

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Abstract

Experimental model systems identified phosphorylation of linker histone variant H1.4 at Ser 27 (H1.4S27p) as a novel mitotic mark set by Aurora B kinase. Here, we examined expression of Aurora B and H1.4S27p in colorectal carcinoma (CRC) cell lines (HCT116, DLD1, Caco-2, HT29) and tissue specimens (n = 36), in relation to microsatellite instability (MSI) status and ploidy. In vitro, Aurora B (pro-/meta-/anaphase) and H1.4S27p (pro-/metaphase) were localized in mitotic figures. The proportion of labeled mitoses was significantly different between cell lines for Aurora B (p = 0.019) but not for H1.4S27p (p = 0.879). For Aurora B, these differences were not associated with an altered Aurora B gene copy number (FISH) or messenger RNA (mRNA) expression level (qRT-PCR). Moreover, Aurora B expression and H1.4S27 phosphorylation were no longer coordinated during metaphase in aneuploid HT29 cells (p = 0.039). In CRCs, immunoreactivity for Aurora B or H1.4S27p did not correlate with T- or N-stage, grade, or MSI status. However, metaphase labeling of H1.4S27p was significantly higher in diploid than in aneuploid CRCs (p = 0.011). Aurora B was significantly correlated with H1.4S27p-positive metaphases in MSI (p = 0.010) or diploid (p = 0.003) CRCs. Finally, combined classification of MSI status and ploidy revealed a significant positive correlation of Aurora B with H1.4S27p in metaphases of diploid/MSI (p = 0.010) and diploid/microsatellite-stable (MSS; p = 0.031) but not of aneuploid/MSS (p = 0.458) CRCs. The present study underlines the functional link of Aurora B expression and H1.4S27p during specific phases of mitosis in diploid and/or MSI-positive CRCs in vitro and in situ. Importantly, the study shows that the coordination between Aurora B expression and phosphorylation of H1.4 at Ser 27 is lost in cycling aneuploid CRC cells.

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References

  1. Boyle P, Langman JS (2000) Epidemiology 321:805–808

    CAS  Google Scholar 

  2. Center MM, Jemal A, Smith RA, Ward E (2009) Worldwide variations in colorectal cancer. CA Cancer J Clin 59:366–378. doi:10.3322/caac.20038

    Article  PubMed  Google Scholar 

  3. Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460. doi:10.1056/NEJMra0804588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Decordier I, Cundari E, Kirsch-Volders M (2008) Mitotic checkpoints and the maintenance of the chromosome karyotype. Mutat Res 651:3–13. doi:10.1016/j.mrgentox.2007.10.020

    Article  CAS  PubMed  Google Scholar 

  5. Bharadwaj R, Yu H (2004) The spindle checkpoint, aneuploidy, and cancer. Oncogene 23:2016–2027. doi:10.1038/sj.onc.1207374

    Article  CAS  PubMed  Google Scholar 

  6. Vader G, Maia AF, Lens SM (2008) The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond. Cell Div 3:10. doi:10.1186/1747-1028-3-10

    Article  PubMed Central  PubMed  Google Scholar 

  7. Lassmann S, Danciu M, Müller M et al (2009) Aurora A is differentially expressed and regulated in chromosomal and microsatellite instable sporadic colorectal cancers. Mod Pathol 22:1385–1397. doi:10.1038/modpathol.2009.111

    Article  CAS  PubMed  Google Scholar 

  8. Vader G, Lens SM (2008) The Aurora kinase family in cell division and cancer. Biochim Biophys Acta 1786:60–72. doi:10.1016/j.bbcan.2008.07.003

    CAS  PubMed  Google Scholar 

  9. Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5:1–10. doi:10.1158/1541-7786

    Article  CAS  PubMed  Google Scholar 

  10. Dar AA, Goff LW, Majid S et al (2010) Aurora kinase inhibitors—rising stars in cancer therapeutics? Mol Cancer Ther 9:268–278. doi:10.1158/1535-7163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Barr AR, Gergely F (2007) Aurora-A: the maker and breaker of spindle poles. J Cell Sci 120:2987–2996. doi:10.1242/jcs.013136

    Article  CAS  PubMed  Google Scholar 

  12. Marumoto T, Zhang D, Saya H (2005) Aurora-A—a guardian of poles. Nat Rev Cancer 5:42–50. doi:10.1038/nrc1526

    Article  CAS  PubMed  Google Scholar 

  13. Herz C, Schlürmann F, Batarello D et al (2012) Occurrence of Aurora A positive multipolar mitoses in distinct molecular classes of colorectal carcinomas and effect of Aurora A inhibition. Mol Carcinog 51:696–710. doi:10.1002/mc.20823

    Article  CAS  PubMed  Google Scholar 

  14. Lingle WL, Barrett SL, Negron VC et al (2002) Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci U S A 99:1978–1983. doi:10.1073/pnas.032479999

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Baba Y, Nosho K (2009) Aurora-A Expression Is Independently Associated with Chromosomal Instability in Colorectal Cancer 1. Neoplasia 11:418–425. doi:10.1593/neo.09154

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Bischoff JR, Anderson L, Zhu Y et al (1998) A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065. doi:10.1093/emboj/17.11.3052

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Burum-Auensen E, DeAngelis PM, Schjølberg AR et al (2008) Reduced level of the spindle checkpoint protein BUB1B is associated with aneuploidy in colorectal cancers. Cell Prolif 41:645–659. doi:10.1111/j.1365-2184.2008.00539.x

    Article  CAS  PubMed  Google Scholar 

  18. Lassmann S, Shen Y, Jütting U et al (2007) Predictive value of Aurora-A/STK15 expression for late stage epithelial ovarian cancer patients treated by adjuvant chemotherapy. Clin Cancer Res 13:4083–4091. doi:10.1158/1078-0432.CCR-06-2775

    Article  CAS  PubMed  Google Scholar 

  19. Andrews PD (2005) Aurora kinases: shining lights on the therapeutic horizon? Oncogene 24:5005–5015. doi:10.1038/sj.onc.1208752

    Article  CAS  PubMed  Google Scholar 

  20. Carvajal RD, Tse A, Schwartz GK (2006) Aurora kinases: new targets for cancer therapy. Clin Cancer Res 12:6869–6875. doi:10.1158/1078-0432.CCR-06-1405

    Article  CAS  PubMed  Google Scholar 

  21. Agnese V, Bazan V, Fiorentino FP et al (2007) The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 18(Suppl 6):vi47–vi52. doi:10.1093/annonc/mdm224

    PubMed  Google Scholar 

  22. Tanaka K (2013) Regulatory mechanisms of kinetochore-microtubule interaction in mitosis. Cell Mol Life Sci 70:559–579. doi:10.1007/s00018-012-1057-7

    Article  CAS  PubMed  Google Scholar 

  23. Adams RR, Maiato H, Earnshaw WC, Carmena M (2001) Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. J Cell Biol 153:865–880

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Nguyen HG, Makitalo M, Yang D et al (2009) Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J 23:2741–2748. doi:10.1096/fj.09-130963

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Kulkarni AA, Loddo M, Leo E et al (2007) DNA replication licensing factors and aurora kinases are linked to aneuploidy and clinical outcome in epithelial ovarian carcinoma. Clin Cancer Res 13:6153–6161. doi:10.1158/1078-0432.CCR-07-0671

    Article  CAS  PubMed  Google Scholar 

  26. Beussel S, Hasenburg A, Bogatyreva L et al (2012) Aurora-B protein expression is linked to initial response to taxane-based first-line chemotherapy in stage III ovarian carcinoma. J Clin Pathol 65:29–35. doi:10.1136/jclinpath-2011-200212

    Article  CAS  PubMed  Google Scholar 

  27. Tuncel H, Shimamoto F, Kaneko Guangying Qi H et al (2012) Nuclear Aurora B and cytoplasmic Survivin expression is involved in lymph node metastasis of colorectal cancer. Oncol Lett 3:1109–1114. doi:10.3892/ol.2012.633

    PubMed Central  PubMed  Google Scholar 

  28. Chieffi P, Cozzolino L, Kisslinger A et al (2006) Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 66:326–333. doi:10.1002/pros.20345

    Article  CAS  PubMed  Google Scholar 

  29. Sorrentino R, Libertini S, Pallante PL et al (2005) Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 90:928–935. doi:10.1210/jc.2004-1518

    Article  CAS  PubMed  Google Scholar 

  30. Kurai M, Shiozawa T, Shih H-C et al (2005) Expression of Aurora kinases A and B in normal, hyperplastic, and malignant human endometrium: Aurora B as a predictor for poor prognosis in endometrial carcinoma. Hum Pathol 36:1281–1288. doi:10.1016/j.humpath.2005.09.014

    Article  CAS  PubMed  Google Scholar 

  31. Le L-T-T VH-L, Nguyen C-H, Molla A (2013) Basal aurora kinase B activity is sufficient for histone H3 phosphorylation in prophase. Biol Open 2:379–386. doi:10.1242/bio.20133079

    Article  Google Scholar 

  32. Hergeth SP, Dundr M, Tropberger P et al (2011) Isoform-specific phosphorylation of human linker histone H1.4 in mitosis by the kinase Aurora B. J Cell Sci 124:1623–1628. doi:10.1242/jcs.084947

    Article  CAS  PubMed  Google Scholar 

  33. Fichter CD, Herz C, Münch C, Opitz OG, Werner M, Lassmann S (2011) Occurrence of multipolar mitoses and association with Aurora-A/-B kinases and p53 mutations in aneuploid esophageal carcinoma cells. BMC Cell Biol 12:13

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Jallepalli PV, Lengauer C (2001) Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 1:109–117. doi:10.1038/35101065

    Article  CAS  PubMed  Google Scholar 

  35. Terada Y (2001) Role of chromosomal passenger complex in chromosome segregation and cytokinesis. Cell Struct Funct 26:653–657. doi:10.1247/csf.26.653

    Article  CAS  PubMed  Google Scholar 

  36. Tatsuka M, Katayama H, Ota T et al (1998) Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 58:4811–4816

    CAS  PubMed  Google Scholar 

  37. Ota T, Suto S, Katayama H et al (2002) Increased mitotic phosphorylation of istone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res 62:5168–5177

    CAS  PubMed  Google Scholar 

  38. Van der Waal MS, Hengeveld RCC, Van der Horst A, Lens SM (2012) Cell division control by the Chromosomal Passenger Complex. Exp Cell Res 318:1407–1420. doi:10.1016/j.yexcr.2012.03.015

    Article  PubMed  Google Scholar 

  39. Qi G, Ogawa I, Kudo Y et al (2007) Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 450:297–302. doi:10.1007/s00428-006-0360-9

    Article  CAS  PubMed  Google Scholar 

  40. Zeitlin SG, Shelby RD, Sullivan KF (2001) CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. J Cell Biol 155:1147–1157. doi:10.1083/jcb.200108125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Takeshita M, Koga T, Takayama K et al (2013) Aurora-B overexpression is correlated with aneuploidy and poor prognosis in non-small cell lung cancer. Lung Cancer 80:85–90. doi:10.1016/j.lungcan.2012.12.018

    Article  PubMed  Google Scholar 

  42. Muleris M, Chalastanis A, Meyer N et al (2008) Chromosomal instability in near-diploid colorectal cancer: a link between numbers and structure. PLoS One 3:e1632. doi:10.1371/journal.pone.0001632

    Article  PubMed Central  PubMed  Google Scholar 

  43. Sasai K, Katayama H, Stenoien DL et al (2004) Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil Cytoskeleton 59:249–263. doi:10.1002/cm.20039

    Article  CAS  PubMed  Google Scholar 

  44. Slattery SD, Mancini MA, Brinkley BR, Hall RM (2009) Aurora-C kinase supports mitotic progression in the absence of Aurora-B. Cell Cycle 8:2984–2994

    Article  PubMed  Google Scholar 

  45. Sabbattini P, Sjoberg M, Nikic S et al (2014) A H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation. Mol Biol Cell 9:1–24. doi:10.1091/mbc.E13-10-0628

    Google Scholar 

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Acknowledgments

The authors thank Ms. A. Schoepflin, K. Thurig, and N. Bittermann for excellent technical support. F. S. was supported by stipend of the University of Freiburg. ALG is member of the integrated research training group (IRTG) of the DFG, CRC992 “Medical Epigenetics”. The study was in part supported by the German Consortium of Translational Research (DKTK) program “Molecular Diagnostics” (to SL, MW), by the DFG CRC992 "Medical Epigenetics (to SL) and the Mushett Family Foundation, Chester NJ/USA (to SL, MW).

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The authors declare no conflict of interest.

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    Authors and Affiliations

    1. Department of Pathology, University Medical Center, Breisacherstrasse 115A, 79106, Freiburg, Germany

      Fahima Sijare, Anna-Lena Geißler, Christiane D. Fichter, Martin Werner & Silke Lassmann

    2. Faculty of Biology, University of Freiburg, Freiburg, Germany

      Fahima Sijare, Anna-Lena Geißler & Christiane D. Fichter

    3. German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

      Anna-Lena Geißler, Martin Werner & Silke Lassmann

    4. Department of Medicine III, University Medical Center Freiburg, Freiburg, Germany

      Sonja P. Hergeth

    5. Institute for Medical Biometry and Statistics, University Medical Center Freiburg, Freiburg, Germany

      Lioudmila Bogatyreva & Dieter Hauschke

    6. Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS UMR 7104, Inserm, Strasbourg, France

      Robert Schneider

    7. Comprehensive Cancer Center Freiburg, University Medical Center, Freiburg, Germany

      Martin Werner & Silke Lassmann

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    Fahima Sijare and Anna-Lena Geißler contributed equally to this work.

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    Supplementary Fig. S1

    Aurora B expression and H1.4S27p levels in diploid and aneuploid CRCs. a Representative diploid CRC (case no. 21, Table

    Table 2 Summary of Aurora B expression and H1.4S27p levels in CRC tissue specimens.
    Full size table
    2) for Aurora B expression and H1.4S27p levels (×10). b Representative aneuploid CRC (case no. 5, Table 2) for Aurora B expression and H1.4S27p levels (×10). Asterisk, enlargement of labelled inserts (×40) (PPTX 2002 kb)

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    Sijare, F., Geißler, AL., Fichter, C.D. et al. Aurora B expression and histone variant H1.4S27 phosphorylation are no longer coordinated during metaphase in aneuploid colorectal carcinomas. Virchows Arch 466, 503–515 (2015). https://doi.org/10.1007/s00428-015-1727-6

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