CtBP2 Promotes Human Cancer Cell Migration by Transcriptional Activation of Tiam1

Overview

Journal Genes Cancer

Specialty Oncology

Date 2012 Dec 25

PMID 23264848

Citations 45

Authors

Seema Paliwal

Ngoc Ho

Daniel Parker

Steven R Grossman

Affiliations

Soon will be listed here.

Abstract

The mammalian COOH-terminal binding proteins (CtBPs) CtBP1 and CtBP2 are metabolically regulated transcriptional co-repressors that are degraded upon acute exposure to the alternative reading frame (ARF) tumor suppressor. We reported previously that CtBP stimulates cell migration in certain contexts via repression of PTEN transcription and activation of the phosphatidylinositol 3-kinase (PI3K) pathway. We have now identified an additional and direct mechanism for CtBP stimulation of cell migration via regulation of T-cell lymphoma invasion and metastasis 1 (Tiam1) protein. Tiam1 is a guanine nucleotide exchange factor (GEF) for Rac GTPase that plays a critical role in regulating cell adhesion, invasion, and migration and has been directly implicated in the promotion of cancer progression and metastasis. We noted a strict positive correlation between CtBP2 and Tiam1 expression levels and that CtBP promotion of cell migration required CtBP-dependent transcriptional activation of Tiam1. RNA interference (RNAi)-mediated knockdown of CtBP2 in human colon or lung carcinoma cells led to decreased Tiam1 protein and mRNA expression, while overexpression of CtBP2 increased Tiam1 expression levels. RNAi and overexpression studies also demonstrated that Tiam1 is a key downstream mediator of CtBP2-mediated cell migration. An analysis of the Tiam1 promoter revealed binding sites for the CtBP-interacting Kruppel-like factor 8 (KLF8), and a Tiam1 promoter luciferase reporter was induced in the presence of both KLF8 and CtBP2, consistent with KLF8-dependent CtBP transactivation of Tiam1. Chromatin immunoprecipitation analyses demonstrated CtBP2 occupancy of the Tiam1 promoter that was dependent on the presence of KLF8. Our results indicate that Tiam1 is a transcriptional activation target of CtBP2 and that this interaction promotes the pro-oncogenic function of CtBP2 leading to cancer cell migration. Transcriptional activation thus plays a role in CtBP pro-oncogenic functions along with the previously characterized CtBP co-repressor function.

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References

Chinnadurai G . The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res. 2009; 69(3):731-4. PMC: 4367538. DOI: 10.1158/0008-5472.CAN-08-3349. View

Minard M, Herynk M, Collard J, Gallick G . The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model. Oncogene. 2005; 24(15):2568-73. DOI: 10.1038/sj.onc.1208503. View

Minard M, Kim L, Price J, Gallick G . The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat. 2004; 84(1):21-32. DOI: 10.1023/B:BREA.0000018421.31632.e6. View

Chen Y, Paliwal S, Draheim K, Grossman S, Lewis B . p19Arf inhibits the invasion of hepatocellular carcinoma cells by binding to C-terminal binding protein. Cancer Res. 2008; 68(2):476-82. PMC: 2376045. DOI: 10.1158/0008-5472.CAN-07-1960. View

Vigil D, Cherfils J, Rossman K, Der C . Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat Rev Cancer. 2010; 10(12):842-57. PMC: 3124093. DOI: 10.1038/nrc2960. View

Liu L, Zhang Q, Zhang Y, Wang S, Ding Y . Lentivirus-mediated silencing of Tiam1 gene influences multiple functions of a human colorectal cancer cell line. Neoplasia. 2006; 8(11):917-24. PMC: 1716017. DOI: 10.1593/neo.06364. View

Parri M, Chiarugi P . Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal. 2010; 8:23. PMC: 2941746. DOI: 10.1186/1478-811X-8-23. View

Lane J, Martin T, Mansel R, Jiang W . The expression and prognostic value of the guanine nucleotide exchange factors (GEFs) Trio, Vav1 and TIAM-1 in human breast cancer. Int Semin Surg Oncol. 2008; 5:23. PMC: 2576462. DOI: 10.1186/1477-7800-5-23. View

Phippen T, Sweigart A, Moniwa M, Krumm A, Davie J, Parkhurst S . Drosophila C-terminal binding protein functions as a context-dependent transcriptional co-factor and interferes with both mad and groucho transcriptional repression. J Biol Chem. 2000; 275(48):37628-37. DOI: 10.1074/jbc.M004234200. View

10.

Sander E, van Delft S, Klooster J, Reid T, van der Kammen R, Michiels F . Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol. 1998; 143(5):1385-98. PMC: 2133078. DOI: 10.1083/jcb.143.5.1385. View

11.

Hu J, Wang Y, Li Y, Wang Y, Han H . [Correlation between T lymphoma invasion and metastasis 1 expression and epithelial-mesenchymal transition in human colorectal carcinomas]. Nan Fang Yi Ke Da Xue Xue Bao. 2009; 29(2):232-5. View

12.

Adithi M, Venkatesan N, Kandalam M, Biswas J, Krishnakumar S . Expressions of Rac1, Tiam1 and Cdc42 in retinoblastoma. Exp Eye Res. 2006; 83(6):1446-52. DOI: 10.1016/j.exer.2006.08.003. View

13.

Chinnadurai G . CtBP family proteins: more than transcriptional corepressors. Bioessays. 2003; 25(1):9-12. DOI: 10.1002/bies.10212. View

14.

Jin W, Scotto K, Hait W, Yang J . Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells. Biochem Pharmacol. 2007; 74(6):851-9. PMC: 1987360. DOI: 10.1016/j.bcp.2007.06.017. View

15.

Cain R, Ridley A . Phosphoinositide 3-kinases in cell migration. Biol Cell. 2008; 101(1):13-29. DOI: 10.1042/BC20080079. View

16.

Zhang X, Jin H, Chen J, Yu L, Li Y, Ding Y . [Relationship between Tiam-1 expression and the biological behaviors of nasopharyngeal carcinoma]. Nan Fang Yi Ke Da Xue Xue Bao. 2009; 29(1):26-8. View

17.

Malliri A, van der Kammen R, Clark K, van der Valk M, Michiels F, Collard J . Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature. 2002; 417(6891):867-71. DOI: 10.1038/nature00848. View

18.

Hildebrand J, Soriano P . Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development. Mol Cell Biol. 2002; 22(15):5296-307. PMC: 133942. DOI: 10.1128/MCB.22.15.5296-5307.2002. View

19.

Heasman S, Ridley A . Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008; 9(9):690-701. DOI: 10.1038/nrm2476. View

20.

Habets G, van der Kammen R, Stam J, Michiels F, Collard J . Sequence of the human invasion-inducing TIAM1 gene, its conservation in evolution and its expression in tumor cell lines of different tissue origin. Oncogene. 1995; 10(7):1371-6. View