Skip to main content

Advertisement

SpringerLink
Log in

Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-κB

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-κB contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in breast cancer-1 (DBC1) protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. DBC1 interacted with IKK-β, stimulating its kinase activity, promoting NF-κB transcriptional activity through the phosphorylation of relA serine-536 and enhancing the expression of the NF-κB target genes, c-FLIP and bcl-xl. Our results indicate that DBC1 is an important co-factor for the control of the IKK-β-NF-κB signaling pathway that regulates anoikis.

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

Similar content being viewed by others

References

  1. Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626

    Article  PubMed  CAS  Google Scholar 

  2. Guadamillas MC, Cerezo A, Del Pozo MA (2011) Overcoming anoikis—pathways to anchorage-independent growth in cancer. J Cell Sci 124:3189–3197

    Article  PubMed  CAS  Google Scholar 

  3. Frisch SM, Schaller M, Cieply B (2013) Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci 126(pt 1):21–29

    Article  PubMed  CAS  Google Scholar 

  4. Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272:177–185

    Article  PubMed  CAS  Google Scholar 

  5. Baldwin AS (2012) Regulation of cell death and autophagy by IKK and NF-kappaB: critical mechanisms in immune function and cancer. Immunol Rev 246:327–345

    Article  PubMed  Google Scholar 

  6. Aggarwal BB, Sung B (2011) NF-kappaB in cancer: a matter of life and death. Cancer Discov 1:469–471

    Article  PubMed  CAS  Google Scholar 

  7. DiDonato JA, Mercurio F, Karin M (2012) NF-kappaB and the link between inflammation and cancer. Immunol Rev 246:379–400

    Article  PubMed  Google Scholar 

  8. Toruner M, Fernandez-Zapico M, Sha JJ, Pham L, Urrutia R et al (2006) Antianoikis effect of nuclear factor-kappaB through up-regulated expression of osteoprotegerin, BCL-2, and IAP-1. J Biol Chem 281:8686–8696

    Article  PubMed  CAS  Google Scholar 

  9. Liu Z, Li H, Wu X, Yoo BH, Yan SR et al (2006) Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells. Oncogene 25:7680–7690

    Article  PubMed  CAS  Google Scholar 

  10. Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T et al (2010) IAP regulation of metastasis. Cancer Cell 17:53–64

    Article  PubMed  CAS  Google Scholar 

  11. Mawji IA, Simpson CD, Hurren R, Gronda M, Williams MA et al (2007) Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation. J Natl Cancer Inst 99:811–822

    Article  PubMed  CAS  Google Scholar 

  12. Yan SR, Joseph RR, Rosen K, Reginato MJ, Jackson A et al (2005) Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells. Oncogene 24:6482–6491

    PubMed  CAS  Google Scholar 

  13. Lin DC, Zhang Y, Pan QJ, Yang H, Shi ZZ et al (2011) PLK1 Is transcriptionally activated by NF-kappaB during cell detachment and enhances anoikis resistance through inhibiting beta-catenin degradation in esophageal squamous cell carcinoma. Clin Cancer Res 17:4285–4295

    Article  PubMed  CAS  Google Scholar 

  14. Howe EN, Cochrane DR, Cittelly DM, Richer JK (2012) miR-200c targets a NF-kappaB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer. PLoS One 7:e49987

    Article  PubMed  CAS  Google Scholar 

  15. Calao M, Burny A, Quivy V, Dekoninck A, Van Lint C (2008) A pervasive role of histone acetyltransferases and deacetylases in an NF-kappaB-signaling code. Trends Biochem Sci 33:339–349

    Article  PubMed  CAS  Google Scholar 

  16. Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappaB signaling pathways. Nat Immunol 12:695–708

    Article  PubMed  CAS  Google Scholar 

  17. Jeong SJ, Pise-Masison CA, Radonovich MF, Park HU, Brady JN (2005) A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 inhibition in the absence of NF-kappaB transcriptional activity. J Biol Chem 280:10326–10332

    Article  PubMed  CAS  Google Scholar 

  18. Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W (1999) IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274:30353–30356

    Article  PubMed  CAS  Google Scholar 

  19. Yang F, Tang E, Guan K, Wang CY (2003) IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J Immunol 170:5630–5635

    PubMed  CAS  Google Scholar 

  20. Adli M, Merkhofer E, Cogswell P, Baldwin AS (2010) IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF-induced/canonical pathway. PLoS One 5:e9428

    Article  PubMed  Google Scholar 

  21. Zannini L, Buscemi G, Kim JE, Fontanella E, Delia D (2012) DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage. J Mol Cell Biol 4:294–303

    Article  PubMed  CAS  Google Scholar 

  22. Hiraike H, Wada-Hiraike O, Nakagawa S, Saji S, Maeda D et al (2011) Expression of DBC1 is associated with nuclear grade and HER2 expression in breast cancer. Exp Ther Med 2:1105–1109

    PubMed  Google Scholar 

  23. Lee H, Kim KR, Noh SJ, Park HS, Kwon KS et al (2011) Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma. Hum Pathol 42:204–213

    Article  PubMed  CAS  Google Scholar 

  24. Kim SH, Kim JH, Yu EJ, Lee KW, Park CK (2012) The overexpression of DBC1 in esophageal squamous cell carcinoma correlates with poor prognosis. Histol Histopathol 27:49–58

    PubMed  CAS  Google Scholar 

  25. Zhang Y, Gu Y, Sha S, Kong X, Zhu H, et al (2013) DBC1 is over-expressed and associated with poor prognosis in colorectal cancer. Int J Clin Oncol. doi:10.1007/s10147-012-0506-5

  26. Kim JE, Chen J, Lou Z (2009) p30 DBC is a potential regulator of tumorigenesis. Cell Cycle 8(18):2932–2935

    Article  PubMed  Google Scholar 

  27. Escande C, Chini CC, Nin V, Dykhouse KM, Novak CM et al (2010) Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice. J Clin Invest 120:545–558

    Article  PubMed  CAS  Google Scholar 

  28. Debnath J, Muthuswamy SK, Brugge JS (2003) Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30:256–268

    Article  PubMed  CAS  Google Scholar 

  29. Shehzad A, Khan S, Sup Lee Y (2012) Curcumin molecular targets in obesity and obesity-related cancers. Future Oncol 8:179–190

    Article  PubMed  CAS  Google Scholar 

  30. Mori N, Yamada Y, Ikeda S, Yamasaki Y, Tsukasaki K et al (2002) Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells. Blood 100:1828–1834

    Article  PubMed  CAS  Google Scholar 

  31. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV (1997) IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 278:866–869

    Article  PubMed  CAS  Google Scholar 

  32. Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R et al (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129:1065–1079

    Article  PubMed  CAS  Google Scholar 

  33. Zhao W, Kruse JP, Tang Y, Jung SY, Qin J et al (2008) Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451:587–590

    Article  PubMed  CAS  Google Scholar 

  34. Kim JE, Chen J, Lou Z (2008) DBC1 is a negative regulator of SIRT1. Nature 451:583–586

    Article  PubMed  CAS  Google Scholar 

  35. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G et al (2004) A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 6:97–105

    Article  PubMed  CAS  Google Scholar 

  36. Sakamoto K, Hikiba Y, Nakagawa H, Hirata Y, Hayakawa Y et al (2013) Promotion of DNA repair by nuclear IKKbeta phosphorylation of ATM in response to genotoxic stimuli. Oncogene 32(14):1854–1862

    Article  PubMed  CAS  Google Scholar 

  37. Alfano D, Iaccarino I, Stoppelli MP (2006) Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 281:17758–17767

    Article  PubMed  CAS  Google Scholar 

  38. Mawji IA, Simpson CD, Gronda M, Williams MA, Hurren R et al (2007) A chemical screen identifies anisomycin as an anoikis sensitizer that functions by decreasing FLIP protein synthesis. Cancer Res 67:8307–8315

    Article  PubMed  CAS  Google Scholar 

  39. Adli M, Baldwin AS (2006) IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylation. J Biol Chem 281:26976–26984

    Article  PubMed  CAS  Google Scholar 

  40. Tsuchiya Y, Asano T, Nakayama K, Kato T Jr, Karin M et al (2010) Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UV-induced NF-kappaB activation. Mol Cell 39:570–582

    Article  PubMed  CAS  Google Scholar 

  41. Lewander A, Gao J, Carstensen J, Arbman G, Zhang H et al (2012) NF-kappaB p65 phosphorylated at serine-536 is an independent prognostic factor in Swedish colorectal cancer patients. Int J Colorectal Dis 27:447–452

    Article  PubMed  Google Scholar 

  42. Bae HJ, Chang YG, Noh JH, Kim JK, Eun JW et al (2012) DBC1 does not function as a negative regulator of SIRT1 in liver cancer. Oncol Lett 4:873–877

    PubMed  CAS  Google Scholar 

  43. Yu EJ, Kim SH, Heo K, Ou CY, Stallcup MR et al (2011) Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor alpha activity and co-activator synergy. Nucleic Acids Res 39:6932–6943

    Article  PubMed  CAS  Google Scholar 

  44. Li Z, Chen L, Kabra N, Wang C, Fang J et al (2009) Inhibition of SUV39H1 methyltransferase activity by DBC1. J Biol Chem 284:10361–10366

    Article  PubMed  CAS  Google Scholar 

  45. Chini CC, Escande C, Nin V, Chini EN (2010) HDAC3 is negatively regulated by the nuclear protein DBC1. J Biol Chem 285:40830–40837

    Article  PubMed  CAS  Google Scholar 

  46. Hiraike H, Wada-Hiraike O, Nakagawa S, Koyama S, Miyamoto Y et al (2010) Identification of DBC1 as a transcriptional repressor for BRCA1. Br J Cancer 102:1061–1067

    Article  PubMed  CAS  Google Scholar 

  47. Trauernicht AM, Kim SJ, Kim NH, Boyer TG (2007) Modulation of estrogen receptor alpha protein level and survival function by DBC-1. Mol Endocrinol 21:1526–1536

    Article  PubMed  CAS  Google Scholar 

  48. Fu J, Jiang J, Li J, Wang S, Shi G et al (2009) Deleted in breast cancer 1, a novel androgen receptor (AR) coactivator that promotes AR DNA-binding activity. J Biol Chem 284:6832–6840

    Article  PubMed  CAS  Google Scholar 

  49. Close P, East P, Dirac-Svejstrup AB, Hartmann H, Heron M et al (2012) DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation. Nature 484:386–389

    Article  PubMed  CAS  Google Scholar 

  50. Nin V, Escande C, Chini CC, Giri S, Camacho-Pereira J et al (2012) Role of deleted in breast cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase. J Biol Chem 287:23489–23501

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

S.M. Frisch was supported by NIH Grant R01CA123359. The flow cytometry core facility (Mary Babb Randolph Cancer Center) was supported by NIH Grants RR020866 and P20 RR16440 and we thank Kathy Brundage for performing the flow-sorting. We also wish to thank Zenkun Lou, Eduardo Chini for the DBC1-knockout cells, Alexey Ivanov, Elena Pugacheva, Jurg Tschopp, Russ Carstens, Yon Rojanasakul and Sierra Talbott for constructs; we also thank the Biochemistry Protein Core for assistance with recombinant protein production.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Mary Babb Randolph Cancer Center, West Virginia University, 1 Medical Center Drive, Campus, Room 2833, Morgantown, WV , 26506, USA

    Sun Hee Park, Philip Riley IV & Steven M. Frisch

  2. Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA

    Steven M. Frisch

Authors
  1. Sun Hee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Riley IV
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven M. Frisch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven M. Frisch.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 493 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, S.H., Riley, P. & Frisch, S.M. Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-κB. Apoptosis 18, 949–962 (2013). https://doi.org/10.1007/s10495-013-0847-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-013-0847-1

Keywords

Search

Navigation