Skip to main content

Advertisement

SpringerLink
Log in

Ankyrin G expression is associated with androgen receptor stability, invasiveness, and lethal outcome in prostate cancer patients

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Ankyrin G (ANK3) is a member of the Ankyrin family, which functions to provide cellular stability by anchoring the cytoskeleton to the plasma membrane. Deregulation of ANK3 expression has been observed in multiple human cancers but its mechanism remains unknown. ANK3 expression in relation to disease progression and patients’ outcome was investigated in two cohorts of prostate cancer (PCA). Mechanistic studies were carried out in vitro and in vivo using several PCA cell lines and the avian embryo model. Silencing ANK3 resulted in significant reduction of cell proliferation through an AR-independent mechanism. Decreased ANK3 expression delayed S phase to G2/M cell cycle transition and reduced the expression of cyclins A and B. However, cells with knocked-down ANK3 exhibited significant increase in cell invasion through an AR-dependent mechanism. Furthermore, we found that ANK3 is a regulator of AR protein stability. ANK3 knockdown also promoted cancer cell invasion and extravasations in vivo using the avian embryo model (p < 0.01). In human samples, ANK3 expression was dramatically upregulated in high grade intraepithelial neoplasia (HGPIN) and localized PCA (p < 0.0001). However, it was downregulated castration resistant stage (p < 0.0001) and showed inverse relation to Gleason score (p < 0.0001). In addition, increased expression of ANK3 in cancer tissues was correlated with better cancer-specific survival of PCA patients (p = 0.012).

Key message

  • Silencing ANK3 results in significant reduction of cell proliferation through an AR-independent mechanism.

  • ANK3 knockdown results in significant increase in cell invasion through an AR-dependent mechanism.

  • ANK3 is a regulator of AR protein stability.

  • ANK3 knockdown also promotes cancer cell invasion and extravasation in vivo using the avian embryo model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30

    Article  PubMed  Google Scholar 

  2. Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31:578–583

    Article  CAS  PubMed  Google Scholar 

  3. Lambert S, Bennett V (1993) From anemia to cerebellar dysfunction. A review of the ankyrin gene family. Eur J Biochem 211:1–6

    Article  CAS  PubMed  Google Scholar 

  4. Peters LL, John KM, Lu FM, Eicher EM, Higgins A, Yialamas M, Turtzo LC, Otsuka AJ, Lux SE (1995) Ank3 (epithelial ankyrin), a widely distributed new member of the ankyrin gene family and the major ankyrin in kidney, is expressed in alternatively spliced forms, including forms that lack the repeat domain. J Cell Biol 130:313–330

    Article  CAS  PubMed  Google Scholar 

  5. Bennett V (1992) Ankyrins. Adaptors between diverse plasma membrane proteins and the cytoplasm. J Biol Chem 267:8703–8706

    CAS  PubMed  Google Scholar 

  6. De Matteis MA, Morrow JS (1998) The role of ankyrin and spectrin in membrane transport and domain formation. Curr Opin Cell Biol 10:542–549

    Article  CAS  PubMed  Google Scholar 

  7. Bennett V, Chen L (2001) Ankyrins and cellular targeting of diverse membrane proteins to physiological sites. Curr Opin Cell Biol 13:61–67

    Article  CAS  PubMed  Google Scholar 

  8. Kordeli E, Lambert S, Bennett V (1995) AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J Biol Chem 270:2352–2359

    Article  CAS  PubMed  Google Scholar 

  9. Hoock TC, Peters LL, Lux SE (1997) Isoforms of ankyrin-3 that lack the NH2-terminal repeats associate with mouse macrophage lysosomes. J Cell Biol 136:1059–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ignatiuk A, Quickfall JP, Hawrysh AD, Chamberlain MD, Anderson DH (2006) The smaller isoforms of ankyrin 3 bind to the p85 subunit of phosphatidylinositol 3’-kinase and enhance platelet-derived growth factor receptor down-regulation. J Biol Chem 281:5956–5964

    Article  CAS  PubMed  Google Scholar 

  11. Grubb MS, Burrone J (2010) Building and maintaining the axon initial segment. Curr Opin Neurobiol 20:481–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lambert S, Davis JQ, Bennett V (1997) Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates. J Neurosci 17:7025–7036

    CAS  PubMed  Google Scholar 

  13. Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, et al. (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40:1056–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Smith EN, Bloss CS, Badner JA, Barrett T, Belmonte PL, Berrettini W, Byerley W, Coryell W, Craig D, Edenberg HJ, et al. (2009) Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry 14:755–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pandey A, Davis NA, White BC, Pajewski NM, Savitz J, Drevets WC, McKinney BA (2012) Epistasis network centrality analysis yields pathway replication across two GWAS cohorts for bipolar disorder. Transl Psychiatry 2:e154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Glinsky GV, Berezovska O, Glinskii AB (2005) Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 115:1503–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bismar TA, Alshalalfa M, Petersen LF, Teng LH, Gerke T, Bakkar A, Al-Mami A, Liu S, Dolph M, Mucci LA, et al. (2014) Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients’ clinical outcome. BJU Int 113:309–319

    Article  CAS  PubMed  Google Scholar 

  18. Kumar S, Park SH, Cieply B, Schupp J, Killiam E, Zhang F, Rimm DL, Frisch SM (2011) A pathway for the control of anoikis sensitivity by E-cadherin and epithelial-to-mesenchymal transition. Mol Cell Biol 31:4036–4051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, MC W, Shimamura T, Perera SA, et al. (2007) LKB1 modulates lung cancer differentiation and metastasis. Nature 448:807–810

    Article  CAS  PubMed  Google Scholar 

  20. Leong HS, Robertson AE, Stoletov K, Leith SJ, Chin CA, Chien AE, Hague MN, Ablack A, Carmine-Simmen K, McPherson VA, et al. (2014) Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep 8:1558–1570

    Article  CAS  PubMed  Google Scholar 

  21. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL, Committee IG (2005) The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 29:1228–1242

  22. Yu M, Sun J, Thakur C, Chen B, Lu Y, Zhao H, Chen F (2014) Paradoxical roles of mineral dust induced gene on cell proliferation and migration/invasion. PLoS One 9:e87998

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gil-Henn H, Patsialou A, Wang Y, Warren MS, Condeelis JS, Koleske AJ (2013) Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo. Oncogene 32:2622–2630

    Article  CAS  PubMed  Google Scholar 

  24. Evdokimova V, Tognon C, Ng T, Sorensen PH (2009) Reduced proliferation and enhanced migration: two sides of the same coin? Molecular mechanisms of metastatic progression by YB-1. Cell Cycle 8:2901–2906

    Article  CAS  PubMed  Google Scholar 

  25. Lehn S, Tobin NP, Berglund P, Nilsson K, Sims AH, Jirstrom K, Harkonen P, Lamb R, Landberg G (2010) Down-regulation of the oncogene cyclin D1 increases migratory capacity in breast cancer and is linked to unfavorable prognostic features. Am J Pathol 177:2886–2897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang W, Goswami S, Sahai E, Wyckoff JB, Segall JE, Condeelis JS (2005) Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol 15:138–145

    Article  CAS  PubMed  Google Scholar 

  27. Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E, Singer RH, Segall JE, Condeelis JS (2004) Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64:8585–8594

    Article  CAS  PubMed  Google Scholar 

  28. Wang W, Wyckoff JB, Goswami S, Wang Y, Sidani M, Segall JE, Condeelis JS (2007) Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res 67:3505–3511

    Article  CAS  PubMed  Google Scholar 

  29. Shiota M, Yokomizo A, Naito S (2011) Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target. J Mol Endocrinol 47:R25–R41

    Article  CAS  PubMed  Google Scholar 

  30. Wagle S, Park SH, Kim KM, Moon YJ, Bae JS, Kwon KS, Park HS, Lee H, Moon WS, Kim JR, et al. (2015) DBC1/CCAR2 is involved in the stabilization of androgen receptor and the progression of osteosarcoma. Sci Rep 5:13144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ramos-Montoya A, Lamb AD, Russell R, Carroll T, Jurmeister S, Galeano-Dalmau N, Massie CE, Boren J, Bon H, Theodorou V, et al. (2014) HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network. EMBO Mol Med 6:651–661

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Balk SP, Knudsen KE (2008) AR, the cell cycle, and prostate cancer. Nucl Recept Signal 6:e001

    PubMed  PubMed Central  Google Scholar 

  33. Vanaja DK, Mitchell SH, Toft DO, Young CY (2002) Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 7:55–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Linn DE, Yang X, Xie Y, Alfano A, Deshmukh D, Wang X, Shimelis H, Chen H, Li W, Xu K, et al. (2012) Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. J Biol Chem 287:22959–22968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

This work was supported in part by the Prostate Cancer Foundation Young Investigator Award (T.A. B). This work was also supported by Prostate cancer Canada and is proudly funded by the Movember Foundation-Grant no. B2013-01.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, Calgary, Canada

    Tingting Wang, Hatem Abou-Ouf, Samar A. Hegazy & Tarek A. Bismar

  2. The Prostate Cancer Centre, Calgary, AB, Canada

    Samar A. Hegazy, Mohammed Alshalalfa, Bryan Donnelly & Tarek A. Bismar

  3. Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

    Samar A. Hegazy

  4. Department of Oncology, University of Alberta, Edmonton, AB, Canada

    Konstantin Stoletov & John Lewis

  5. Department of Urology, University of Calgary, Calgary, AB, Canada

    Bryan Donnelly

  6. Departments of Oncology, Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada

    Tarek A. Bismar

  7. Southern Alberta Cancer Research Institute and Tom Baker Cancer Center, Calgary, AB, Canada

    Tarek A. Bismar

  8. Departments of Pathology & Laboratory Medicine and Oncology, Faculty of Medicine, University of Calgary, Rockyview General Hospital, 7007 – 14th Street SW, Calgary, AB, T2V 1P9, Canada

    Tarek A. Bismar

Authors
  1. Tingting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hatem Abou-Ouf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samar A. Hegazy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammed Alshalalfa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Konstantin Stoletov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bryan Donnelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tarek A. Bismar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tarek A. Bismar.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare in this study.

Additional information

Tingting Wang and Hatem Abou-Ouf these authors contributed equally

Electronic supplementary material

ESM 1

(PDF 306 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, T., Abou-Ouf, H., Hegazy, S.A. et al. Ankyrin G expression is associated with androgen receptor stability, invasiveness, and lethal outcome in prostate cancer patients. J Mol Med 94, 1411–1422 (2016). https://doi.org/10.1007/s00109-016-1458-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-016-1458-4

Keywords

Search

Navigation