Abstract
Diminished expression of the metastasis suppressor protein RKIP was previously reported in a number of cancers. The underlying mechanism remains unknown. Here, we show that the expression of RKIP negatively correlates with that of Snail zinc-transcriptional repressor, a key modulator of normal and neoplastic epithelial–mesenchymal transition (EMT) program. With a combination of loss-of-function and gain-of-function approaches, we showed that Snail repressed the expression of RKIP in metastatic prostate cancer cell lines. The effect of Snail on RKIP was on the level of transcriptional initiation and mediated by a proximal E-box on the RKIP promoter. Our results therefore suggest that RKIP is a novel component of the Snail transcriptional regulatory network important for the progression and metastasis of cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Al-Mulla F, Hagan S, Behbehani AI, Bitar MS, George SS, Going JJ et al. (2006). Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. J Clin Oncol 24: 5672–5679.
Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J et al. (2000). The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2: 84–89.
Baylin SB, Herman JG . (2000). DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16: 168–174.
Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J et al. (2002). Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21: 3241–3246.
Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. (2000). The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2: 76–83.
Chatterjee D, Bai Y, Wang Z, Beach S, Mott S, Roy R et al. (2004). RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J Biol Chem 279: 17515–17523.
De Craene B, van Roy F, Berx G . (2005). Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal 17: 535–547.
Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K et al. (2001). Delineation of prognostic biomarkers in prostate cancer. Nature 412: 822–826.
Fu Z, Kitagawa Y, Shen R, Shah R, Mehra R, Rhodes D et al. (2005). Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Prostate 66: 248–256.
Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z et al. (2003). Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 95: 878–889.
Grimes HL, Chan TO, Zweidler-McKay PA, Tong B, Tsichlis PN . (1996). The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol Cell Biol 16: 6263–6272.
Hegan S, Al-Mulla F, Mallon E, Oien KA, Ferrier R, Gusterson B et al. (2005). Reduction of Raf-1 kinase inhibitor protein (RKIP) expression in breast cancer metastases. Clin Cancer Res 11: 7392–7397.
Herman JG, Baylin SB . (2000). Promoter-region hypermethylation and gene silencing in human cancer. Curr Top Microbiol Immunol 249: 35–54.
Jiao W, Miyazaki K, Kitajima Y . (2002). Inverse correlation between E-cadherin and Snail expression in hepatocellular carcinoma cell lines in vitro and in vivo. Br J Cancer 86: 98–101.
Jorda M, Olmeda D, Vinyals A, Valero E, Cubillo E, Llorens A et al. (2005). Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci 118: 3371–3385.
Kajita M, McClinic KN, Wade PA . (2004). Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 24: 7559–7566.
Knight RD, Shimeld SM . (2001). Identification of conserved C2H2 zinc-finger gene families in the Bilateria. Genome Biol 2, RESEARCH0016.
Lee HC, Tian B, Sedivy JM, Wands JR, Kim M . (2006). Loss of raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 131: 1208–1217.
Nakayama H, Scott IC, Cross JC . (1998). The transition to endoreduplication in trophoblast giant cells is regulated by the mSNA zinc finger transcription factor. Dev Biol 199: 150–163.
Nieto MA . (2002). The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3: 155–166.
Park S, Yeung ML, Beach S, Shields JM, Yeung KC . (2005). RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24: 3535–3540.
Peinado H, Olmeda D, Cano A . (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7: 415–428.
Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK . (2001). Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem 276: 24661–24666.
Schuierer MM, Bataille F, Hagan S, Kolch W, Bosserhoff AK . (2004). Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. Cancer Res 64: 5186–5192.
Schuierer MM, Bataille F, Weiss TS, Hellerbrand C, Bosserhoff AK . (2006). Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol Rep 16: 451–456.
Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X et al. (2001). Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409: 207–211.
Thiery JP . (2002). Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.
Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA . (2004). Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18: 1131–1143.
Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R et al. (2001). Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol 37: 65–71.
Zhang L, Fu Z, Binkley C, Giordano T, Burant CF, Logsdon CD et al. (2004). Raf kinase inhibitory protein inhibits beta-cell proliferation. Surgery 136: 708–715.
Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M et al. (2004). Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat Cell Biol 6: 931–940.
Acknowledgements
We thank Stephen J Weiss and Mien-Chie Hung for plasmid constructs. We also acknowledge Chinnaiyan's lab and Robert Trumbly for help in studying the expression correlation of RKIP and Snail in prostate cancer. This work was supported by NIH grants to KCY (R01 GM64767) and ETK (R01 CA098513); and a UTHSC Translational Research Stimulation Award, to KCY. AD and WK are supported by the Cancer Research UK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Beach, S., Tang, H., Park, S. et al. Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene 27, 2243–2248 (2008). https://doi.org/10.1038/sj.onc.1210860
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210860
Keywords
This article is cited by
-
Molecular mechanisms of neuroendocrine differentiation in prostate cancer progression
Journal of Cancer Research and Clinical Oncology (2022)
-
Piperine inhibits colorectal cancer migration and invasion by regulating STAT3/Snail-mediated epithelial–mesenchymal transition
Biotechnology Letters (2020)
-
Expression and clinical significance of SNAI1 and ZEB1 genes in acute myeloid leukemia patients
Molecular Biology Reports (2019)
-
Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma
Journal of Experimental & Clinical Cancer Research (2017)
-
Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT
Cell Death & Disease (2017)