Abstract
O-class forkhead box (FOXO) transcription factors are critical regulators of diverse cellular processes, including apoptosis, cell-cycle arrest, DNA damage repair and oxidative stress resistance. Here, we show that FOXO1 and FOXO3a have an essential function in promoting cell detachment-induced anoikis, resistance to which is implicated in cancer development and metastasis. In contrast, the oncoprotein cyclin D1 inhibits anoikis. We further show that cyclin D1 interacts with FOXO proteins and impedes their transcriptional regulatory and anoikis-promoting functions. This effect of cyclin D1 requires its transcription repression domain but is independent of cyclin-dependent kinases CDK4 and CDK6. Moreover, we show that cancer-derived mutants of cyclin D1 are much more stable than wild-type cyclin D1 under anchorage-independent conditions and possess a greater antagonistic effect on FOXO-regulated anoikis and anchorage-independent growth of cancer cells. These data suggest that cyclin D1 may have a critical function in tumorigenesis and cancer metastasis by inhibiting the anoikis-promoting function of FOXO proteins.
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Abbreviations
- FOXO:
-
O-class forkhead box transcription factor
- CDK:
-
cyclin-dependent kinase
- ECM:
-
extracellular matrix
- siRNA:
-
small inference RNA
- FasL:
-
Fas ligand
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
- PARP:
-
poly(ADP-ribose) polymerase
- RB:
-
retinoblastoma protein
- RD:
-
transcription repression domain
- HA:
-
hemagglutinin
- PCR:
-
polymerase chain reaction
References
Schwartz MA . Integrins, oncogenes, and anchorage independence. J Biol Chem 1997; 139: 575–578.
Frisch SM, Ruoslahti E . Integrins and anoikis. Curr Opin Cell Biol 1997; 9: 701–706.
Giancotti FG, Ruoslahti E . Integrin signaling. Science 1999; 285: 1028–1032.
Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J et al. Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 2003; 5: 733–740.
Mailleux AA, Overholtzer M, Schmelzle T, Bouillet P, Strasser A, Brugge JS . BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms. Dev Cell 2007; 12: 221–234.
Li Z, Zhao J, Du Y, Park HR, Sun SY, Bernal-Mizrachi L et al. Down-regulation of 14-3-3 zeta suppresses anchorage-independent growth of lung cancer cells through anoikis activation. Proc Natl Acad Sci USA 2008; 105: 162–167.
Woods NT, Yamaguchi H, Lee FY, Bhalla KN, Wang HG . Anoikis, initiated by Mcl-1 degradation and Bim induction, is deregulated during oncogenesis. Cancer Res 2007; 67: 10744–10752.
Greer EL, Brunet A . FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410–7425.
Gilley J, Coffer PJ, Ham J . FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 2003; 162: 613–622.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–868.
Modur V, Nagarajan R, Evers BM, Milbrandt J . FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem 2002; 277: 47928–47937.
Huang H, Tindall DJ . Dynamic FoxO transcription factors. J Cell Sci 2007; 120: 2479–2487.
Sherr CJ . Cancer cell cycles. Science 1996; 274: 1672–1677.
Weinstein IB . Cancer. Addiction to oncogenes–the Achilles heal of cancer. Science 2002; 297: 63–64.
Yu Q, Geng Y, Sicinski P . Specific protection against breast cancers by cyclin D1 ablation. Nature 2001; 411: 1017–1021.
Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV . Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994; 369: 669–671.
Creighton CJ . Multiple oncogenic pathway signatures show coordinate expression patterns in human prostate tumors. PLoS ONE 2008; 3: e1816.
Sherr CJ, Roberts JM . Living with or without cyclins and cyclin-dependent kinases. Genes Dev 2004; 18: 2699–2711.
Ewen ME, Lamb J . The activities of cyclin D1 that drive tumorigenesis. Trends Mol Med 2004; 10: 158–162.
Huang H, Regan KM, Lou Z, Chen J, Tindall DJ . CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 2006; 314: 294–297.
Frisch SM, Francis H . Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124: 619–626.
Kim HR, Lin HM, Biliran H, Raz A . Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res 1999; 59: 4148–4154.
Weng Z, Xin M, Pablo L, Grueneberg D, Hagel M, Bain G et al. Protection against anoikis and down-regulation of cadherin expression by a regulatable beta-catenin protein. J Biol Chem 2002; 277: 18677–18686.
Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R . Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 2006; 125: 665–677.
Liu P, Kao TP, Huang H . CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene 2008; 27: 4733–4744.
Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV, Kittrell FS et al. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 2003; 114: 323–334.
Knudsen KE, Diehl JA, Haiman CA, Knudsen ES . Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 2006; 25: 1620–1628.
Radu A, Neubauer V, Akagi T, Hanafusa H, Georgescu MM . PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol Cell Biol 2003; 23: 6139–6149.
Liu P, Li S, Gan L, Kao TP, Huang H . A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells. Cancer Res 2008; 68: 10290–10299.
Benzeno S, Lu F, Guo M, Barbash O, Zhang F, Herman JG et al. Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1. Oncogene 2006; 25: 6291–6303.
Gladden AB, Woolery R, Aggarwal P, Wasik MA, Diehl JA . Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 2006; 25: 998–1007.
Lin DI, Lessie MD, Gladden AB, Bassing CH, Wagner KU, Diehl JA . Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis. Oncogene 2008; 27: 1231–1242.
Liotta LA, Kohn E . Anoikis: cancer and the homeless cell. Nature 2004; 430: 973–974.
Aggarwal P, Lessie MD, Lin DI, Pontano L, Gladden AB, Nuskey B et al. Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev 2007; 21: 2908–2922.
Diehl JA, Zindy F, Sherr CJ . Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997; 11: 957–972.
Drobnjak M, Osman I, Scher HI, Fazzari M, Cordon-Cardo C . Overexpression of cyclin D1 is associated with metastatic prostate cancer to bone. Clin Cancer Res 2000; 6: 1891–1895.
Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J et al. A central domain of cyclin D1 mediates nuclear receptor corepressor activity. Oncogene 2005; 24: 431–444.
Klier M, Anastasov N, Hermann A, Meindl T, Angermeier D, Raffeld M et al. Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2. Leukemia 2008; 22: 2097–2105.
Sauter D, Himmelsbach K, Kriegs M, Carvajal Yepes M, Hildt E . Localization determines function: N-terminally truncated NS5A fragments accumulate in the nucleus and impair HCV replication. J Hepatol 2009; 50: 861–871.
Acknowledgements
We thank DJ Tindall, KL Guan, M Pagano, CY Young, and SW Hayward for plasmids and cell lines, Y Shimizu, V Bardwell, KL Schwertfeger, SM Dehm and members of Huang laboratory, especially LR Bohrer for critical reading of the manuscript. This work was supported in part by funds from the Department of Defense (W81XWH-07-1-0137 and PC080591) and the Brainstorm Award from the University of Minnesota Masonic Cancer Center (to HH), the National Institutes of Health (CA82295 to JBM and CA099996 to KEK), and the National Natural Science Foundation of China (30500109 to LG). All authors claim no conflict of interest with this study.
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Gan, L., Liu, P., Lu, H. et al. Cyclin D1 promotes anchorage-independent cell survival by inhibiting FOXO-mediated anoikis. Cell Death Differ 16, 1408–1417 (2009). https://doi.org/10.1038/cdd.2009.86
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DOI: https://doi.org/10.1038/cdd.2009.86
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