Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence1,2, and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of β-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of β-catenin–reptin requires both increased β-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of β-catenin–reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex3,4,5,6,7,8 that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of β-catenin–reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-κB target genes.
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Shevde, L. A. & Welch, D. R. Metastasis suppressor pathways-an evolving paradigm. Cancer Lett. 198, 1–20 (2003)
Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cell. Nature Rev. Cancer 3, 55–63 (2002)
Feng, Y., Lee, N. & Fearon, E. R. Tip49 regulates β-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. Cancer Res. 63, 8726–8734 (2003)
Bauer, A., Huber, O. & Kemler, R. Pontin52, an interaction partner of β-catenin binds to the TATA box binding protein. Proc. Natl Acad. Sci. USA 95, 14787–14792 (1998)
Bauer, A. et al. Pontin52 and Reptin52 function as antagonistic regulators of β-catenin signaling activity. EMBO J. 19, 6121–6130 (2000)
Wood, M. A., McMahon, S. B. & Cole, M. D. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. Mol. Cell 5, 321–330 (2000)
Rottbauer, W. et al. Reptin and pontin antagonistically regulate heart growth in zebrafish embryos. Cell 111, 661–672 (2002)
Ikura, T. et al. Involvement of the Tip60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000)
Petrylak, D. P. Metastases suppressors and prostate cancer. Nature Med. 1, 739–740 (1995)
Dong, J.-T. et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884–886 (1995)
Dong, J.-T. et al. Down-regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelic loss. Cancer Res. 56, 4387–4390 (1996)
Baek, S. H. et al. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein. Cell 110, 55–67 (2002)
Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001)
Hannon, G. J. RNA interference. Nature 418, 244–251 (2002)
Aberle, H., Bauer, A., Stappert, J., Kispert, A. & Kemler, R. β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16, 3797–3804 (1997)
Orford, K., Crockett, C., Jensen, J. P., Weissman, A. M. & Byers, S. W. Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. J. Biol. Chem. 272, 24735–24738 (1997)
Cheshire, D. R. & Isaacs, W. B. β-Catenin signaling in prostate cancer: an early perspective. Endocr. Relat. Cancer 10, 537–560 (2003)
Clever, H. Wnt breakers in colon cancer. Cancer Cell 5, 5–6 (2004)
Moon, R. T., Bowerman, B., Boutros, M. & Perrimon, N. The promise and perils of Wnt signaling through β-catenin. Science 296, 1644–1646 (2002)
Chesire, D. R., Ewing, C. M., Gage, W. R. & Isaacs, W. B. In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis. Oncogene 21, 2679–2694 (2002)
Deng, J. et al. β-Catenin interacts with and inhibits NF-κB in human colon and breast cancer. Cancer Cell 2, 323–334 (2002)
Li, J. et al. Novel NEMO/IκB kinase and NF-κB target genes at the pre-B to immature B cell transition. J. Biol. Chem. 276, 18579–18590 (2001)
Albini, A. et al. A rapid in vitro assay for quantiating the invasive potential of tumor cells. Cancer Res. 47, 3239–3245 (1987)
Kobayashi, H. et al. Inhibition of in vitro ovarian cancer cell invasion by modulation of urokinase-type plasminogen activator and cathespin B. Cancer Res. 52, 3610–3614 (1992)
Madrid, L. V. & Baldwin, A. S. Jr Regulation of NF-κB by oncoproteins and tumor suppressor protein. Methods Mol. Biol. 223, 523–532 (2003)
We thank A. Hoffman for providing p50-knockout immortalized 3T3 cells; E. H. Koo and colleague for making KAI1-expressing LNCaP cells; D. A. Galloway for HPV-E6/E7 retroviral constructs; J.-T. Dong for KAI1 promoter clone; L. B. Owen-Schaub for Fas promoter reporter constructs; M.-C. Hung for mutant β-catenin constructs; K. Matsumoto for 293IL-RI cells; K. I. Kim, Y. K. Park and J. M. Lee for critical reading; and J. Hightower and M. Fisher for figure and manuscript preparation. We acknowledge support from the National R&D programme for cancer control from Ministry of Health & Welfare, Korea Research Foundation grant, and the BK21 Research Fellowship from the Ministry of Education and Human Resources Development (S.H.B.), the NIH (M.G.R., C.L.S., D.W.R.), and the Prostate Cancer Foundation (PCF) and the National Cancer Institute (NCI) (M.G.R.). M.G.R. is an HHMI Investigator.
The authors declare that they have no competing financial interests.
Primary tumour weights in prostate were comparable in both control vector-expressing and KAI1-expressing cell tumours. (GIF 24 kb)
Tip60 was overexpressed in LNCaP cells and immunoblot assay confirmed the expression of Tip60. Validation of specific knock-down effects of Tip60 and pontin by specific shRNA was shown. (GIF 69 kb)
A constitutive active mutant of β-catenin on Tip60 was overexpressed in RWPE1 cells or 293 cells and immunoblot confirmed the overexpression of β-catenin. Other target promoter activated by Tip60 in the presence of high levels of β-catenin was shown. Increase of β-catenin expression in the nucleus did not change the localization of Tip60. (GIF 234 kb)
Histone deacetylase is crucial for the repressive function of reptin. Validation of function of shRNAs against β-catenin, reptin, HDAC1, or HDAC3 by immunoblot analysis was shown. Both GST-pulldown assay and in vivo immunoprecipitation assays revealed that the crucial region of reptin for binding to HDAC1. (GIF 322 kb)
The PC-3 cells were used in Matrigel invasion assay. The PC-3 cells exhibited no reduction of invaded cells in response to IL-1β but increase of Tip60 expression exhibited an 80% decrease in Matrigel invasion compared to the non-treated control. (GIF 151 kb)
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