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We previously described the novel zinc finger protein ZKSCAN3 as a new “driver” of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Met-related tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin β4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin β4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin β4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin β4 promoter in vitro and in vivo, and the integrin β4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin β4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin β4. We previously described the novel zinc finger protein ZKSCAN3 as a new “driver” of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Met-related tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin β4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin β4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin β4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin β4 promoter in vitro and in vivo, and the integrin β4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin β4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin β4. Sporadic colorectal cancer largely reflects aberrantly activated pathways leading to unrestrained growth. In the Wnt pathway, stabilized β-catenin together with T cell factor-4 and lymphoid enhancer factor-1 DNA-binding proteins (1.Heyer J. Yang K. Lipkin M. Edelmann W. Kucherlapati R. Oncogene. 1999; 18: 5325-5333Crossref PubMed Scopus (105) Google Scholar) trans-activates target genes (2.Korinek V. Barker N. Morin P.J. van Wichen D. de Weger R. Kinzler K.W. Vogelstein B. Clevers H. Science. 1997; 275: 1784-1787Crossref PubMed Scopus (2937) Google Scholar), causal for growth. Mutation-activated K-Ras (3.Aktas H. Cai H. Cooper G.M. Mol. Cell. Biol. 1997; 17: 3850-3857Crossref PubMed Scopus (370) Google Scholar) also promotes tumor growth via the MAPK 2The abbreviations used are: MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor; CAST-ing, cyclic amplification and selection of targets; EMSA, electrophoretic mobility shift assay; KRAB, Kruppel-associated box; MST1R, c-Met-related tyrosine kinase; shRNA, short hairpin RNA; wt, wild type; mt, mutant; kb, kilobase(s); RT, reverse transcription; Q-PCR, quantitative-PCR. pathway, whereas the mutation-disabled type II transforming growth factor (TGF-β) receptor gene (TGF-β RII) (signaling through the MADH-encoded Smad transcription factors (4.Derynck R. Akhurst R.J. Balmain A. Nat. Genet. 2001; 29: 117-129Crossref PubMed Scopus (1963) Google Scholar)) is incapable of restraining proliferation. Targeting of the p53 tumor suppressor also contributes to the pathogenesis of this cancer, as damaged cells are unable to arrest for DNA repair (5.Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6740) Google Scholar), thereby accumulating DNA damage and mutation of key genes crucial to tumor development/progression. Notwithstanding these landmark observations, recent studies (6.Wood L.D. Parsons D.W. Jones S. Lin J. Sjoblom T. Leary R.J. Shen D. Boca S.M. Barber T. Ptak J. Silliman N. Szabo S. Dezso Z. Ustyanksky V. Nikolskaya T. Karchin R. Wilson P.A. Kaminker J.S. Zhang Z. Croshaw R. Willis J. Dawson D. Shipitsin M. Willson J.K. Sukumar S. Polyak K. Park B.H. Pethiyagoda C.L. Pant P.V. Ballinger D.G. Sparks A.B. Hartigan J. Smith D.R. Suh E. Papadopoulos N. Buckhaults P. Markowitz S.D. Parmigiani G. Kinzler K.W. Velculescu V.E. Vogelstein B. Science. 2007; 318: 1108-1113Crossref PubMed Scopus (2577) Google Scholar, 7.Tomlinson I.P. Webb E. Carvajal-Carmona L. Broderick P. Kemp z. Spain S. Penegar S. Chandler I. Gorman M. Gorman M. Wood W. Barclay E. Lubbe S. Martin L. Sellick G. Jaeger E. Hubner R. Wild R. Rowan A. Fielding S. Howarth K. Corgi C. Silver A. Atkin W. Muir K. Logan R. Kerr D. Johnstone E. Sieber O. Gray R. Thomas H. Peto J. Cazier J.-B. Houlston R. Nat. Genet. 2007; 39: 984-988Crossref PubMed Scopus (703) Google Scholar, 8.Parsons D.W. Wang T.-L. Samuels Y. Bardelli A. Cummins J.M. DeLong L. Silliman N. Ptak J. Szabo S. Willson J.K.V. Markowitz S. Kinzler K.W. Vogelstein B. Lengauer C. Velculescu V.E. Nature. 2005; 436: 792Crossref PubMed Scopus (491) Google Scholar, 9.Samuels Y. Diaz L.A. Schmidt-Kittler O. Cummins J.M. DeLong L. Chong I. Rago C. Huso D.L. Lengauer C. Kinzler K.W. Vogelstein B. Velculescu V.E. Cancer Cell. 2005; 7: 561-573Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar, 10.Zanke B.W. Greenwood C.M.T. Rangrej J. Kustra R. Tenesa A. Farrington S.M. Prendergast J. Olschwang S. Chiang T. Crowdy E. Ferretti V. Laflamme P. Sundararajan S. Roumy S. Olivier J.F. Robidoux F. Sladek R. Montpetit A. Campbell P. Bezieau S. G. M. P. J. B. R. J. Campbell H. H. M. E. C. B. E. S. J. Thomas G. S. Nat. Genet. 2007; 39: PubMed Scopus Google Scholar, H. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) that the of this the of gene in to cancer and progression I.P. Webb E. Carvajal-Carmona L. Broderick P. Kemp z. Spain S. Penegar S. Chandler I. Gorman M. Gorman M. Wood W. Barclay E. Lubbe S. Martin L. Sellick G. Jaeger E. Hubner R. Wild R. Rowan A. Fielding S. Howarth K. Corgi C. Silver A. Atkin W. Muir K. Logan R. Kerr D. Johnstone E. Sieber O. Gray R. Thomas H. Peto J. Cazier J.-B. Houlston R. Nat. Genet. 2007; 39: 984-988Crossref PubMed Scopus (703) Google Scholar, 10.Zanke B.W. Greenwood C.M.T. Rangrej J. Kustra R. Tenesa A. Farrington S.M. Prendergast J. Olschwang S. Chiang T. Crowdy E. Ferretti V. Laflamme P. Sundararajan S. Roumy S. Olivier J.F. Robidoux F. Sladek R. Montpetit A. Campbell P. Bezieau S. G. M. P. J. B. R. J. Campbell H. H. M. E. C. B. E. S. J. Thomas G. S. Nat. Genet. 2007; 39: PubMed Scopus Google several genes in the protein kinase kinase and phosphatidyl 3-kinase pathways are D.W. Wang T.-L. Samuels Y. Bardelli A. Cummins J.M. DeLong L. Silliman N. Ptak J. Szabo S. Willson J.K.V. Markowitz S. Kinzler K.W. Vogelstein B. Lengauer C. Velculescu V.E. Nature. 2005; 436: 792Crossref PubMed Scopus (491) Google Scholar), and mutation of of the genes the of in the growth factor and tumor progression Y. Diaz L.A. Schmidt-Kittler O. Cummins J.M. DeLong L. Chong I. Rago C. Huso D.L. Lengauer C. Kinzler K.W. Vogelstein B. Velculescu V.E. Cancer Cell. 2005; 7: 561-573Abstract Full Text Full Text PDF PubMed Scopus (740) Google of the receptor by of in colorectal cancer and of of factor a candidate tumor by promoter and to progression of this A. L. N. P. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. 2007; Full Text Full Text PDF PubMed Scopus Google Moreover, for nucleotide identified a I.P. Webb E. Carvajal-Carmona L. Broderick P. Kemp z. Spain S. Penegar S. Chandler I. Gorman M. Gorman M. Wood W. Barclay E. Lubbe S. Martin L. Sellick G. Jaeger E. Hubner R. Wild R. Rowan A. Fielding S. Howarth K. Corgi C. Silver A. Atkin W. Muir K. Logan R. Kerr D. Johnstone E. Sieber O. Gray R. Thomas H. Peto J. Cazier J.-B. Houlston R. Nat. Genet. 2007; 39: 984-988Crossref PubMed Scopus (703) Google Scholar, 10.Zanke B.W. Greenwood C.M.T. Rangrej J. Kustra R. Tenesa A. Farrington S.M. Prendergast J. Olschwang S. Chiang T. Crowdy E. Ferretti V. Laflamme P. Sundararajan S. Roumy S. Olivier J.F. Robidoux F. Sladek R. Montpetit A. Campbell P. Bezieau S. G. M. P. J. B. R. J. Campbell H. H. M. E. C. B. E. S. J. Thomas G. S. Nat. Genet. 2007; 39: PubMed Scopus Google Wood (6.Wood L.D. Parsons D.W. Jones S. Lin J. Sjoblom T. Leary R.J. Shen D. Boca S.M. Barber T. Ptak J. Silliman N. Szabo S. Dezso Z. Ustyanksky V. Nikolskaya T. Karchin R. Wilson P.A. Kaminker J.S. Zhang Z. Croshaw R. Willis J. Dawson D. Shipitsin M. Willson J.K. Sukumar S. Polyak K. Park B.H. Pethiyagoda C.L. Pant P.V. Ballinger D.G. Sparks A.B. Hartigan J. Smith D.R. Suh E. Papadopoulos N. Buckhaults P. Markowitz S.D. Parmigiani G. Kinzler K.W. Velculescu V.E. Vogelstein B. Science. 2007; 318: 1108-1113Crossref PubMed Scopus (2577) Google Scholar) that the of colorectal cancer is of a gene with a of gene the and of this In a recent for of colorectal cancer we identified ZKSCAN3 to for PubMed Scopus Google Scholar)) as a novel gene the progression of this L. T. A. G. Cancer PubMed Scopus Google the mechanism by ZKSCAN3 colorectal tumorigenicity and progression the predicted ZKSCAN3 protein included zinc and of proteins that gene expression K. M. C. K. H. 39: PubMed Scopus Google Scholar, Y. Y. Yang Z. Wang Y. Z. Wang Z. W. C. Mol. Biol. PubMed Scopus Google Scholar, H. C. J. Wang Y. D. Y. J. W. Y. M. PubMed Scopus Google Scholar), we hypothesized that this zinc finger protein regulates the expression of genes favoring tumor progression. 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Cancer PubMed Scopus Google Scholar), the underlying mechanism the ZKSCAN3 protein of transcription factors, we hypothesized that the protein is regulatory for genes favoring colorectal cancer progression. in cells with a ZKSCAN3 with colorectal L. T. A. G. Cancer PubMed Scopus Google Scholar) and as for a of gene We cyclic amplification and selection of targets to identify a DNA binding ZKSCAN3 protein with a random oligonucleotide library were and the to of In the were and to with protein in the were and the S. G.M. J. Mol. Biol. PubMed Scopus Google Scholar), a DNA binding of and of ZKSCAN3 identify candidate downstream targets, we expression using RNA L. T. A. G. Cancer PubMed Scopus Google Scholar) colon cancer cells the ZKSCAN3 the ZKSCAN3 and a whereas ZKSCAN3 expression in these cells tumor in and are L. T. A. G. Cancer PubMed Scopus Google factors and and gene expression K. J. Y. J. M. Y. W. B. Zhang N. Y. L. PubMed Scopus Google Scholar, C. Y. Yang S. B. H. Shen F. 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Cancer PubMed Scopus Google ZKSCAN3 the DNA binding motif that with whereas the with the ZKSCAN3 binding that the of the integrin β4 is bound with ZKSCAN3. Moreover, this ZKSCAN3 binding regulatory for expression because a reporter by of the integrin β4-derived motif the activated by ZKSCAN3 in cells ZKSCAN3 activated a by the of the integrin β4 of the enhancer and the ZKSCAN3 binding A. T. M. Y. K. S. J. Biol. Full Text Full Text PDF PubMed Scopus Google Thus, integrin β4 is a direct downstream target of ZKSCAN3. of Integrin β4 the of ZKSCAN3 to in and in integrin β4 in the of ZKSCAN3 cells were with a integrin Cancer 2005; PubMed Scopus Google ZKSCAN3 induced integrin β4 and the integrin reduced integrin β4 in cells the ZKSCAN3 the 2 and integrin β4 knockdown countered the anchorage-independent growth as a phosphatidyl 3-kinase integrin β4 in cells the ZKSCAN3 reduced colony this of the ZKSCAN3 and the that for knockdown of the cells integrin reduced growth To these we the cells with the integrin the ZKSCAN3 a of tumorigenicity as by a in tumor this tumor with ZKSCAN3 expression and by knockdown of integrin β4 these integrin β4 as downstream target of ZKSCAN3 that contributes to the a ZKSCAN3 several genes including that were also modulated by ZKSCAN3. of in a for tumor with RNA with the cells the expression a of the ZKSCAN3 knockdown in ZKSCAN3 L. T. A. G. 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Polyak K. Park B.H. Pethiyagoda C.L. Pant P.V. Ballinger D.G. Sparks A.B. Hartigan J. Smith D.R. Suh E. Papadopoulos N. Buckhaults P. Markowitz S.D. Parmigiani G. Kinzler K.W. Velculescu V.E. Vogelstein B. Science. 2007; 318: 1108-1113Crossref PubMed Scopus (2577) Google Scholar, 7.Tomlinson I.P. Webb E. Carvajal-Carmona L. Broderick P. Kemp z. Spain S. Penegar S. Chandler I. Gorman M. Gorman M. Wood W. Barclay E. Lubbe S. Martin L. Sellick G. Jaeger E. Hubner R. Wild R. Rowan A. Fielding S. Howarth K. Corgi C. Silver A. Atkin W. Muir K. Logan R. Kerr D. Johnstone E. Sieber O. Gray R. Thomas H. Peto J. Cazier J.-B. Houlston R. Nat. Genet. 2007; 39: 984-988Crossref PubMed Scopus (703) Google Scholar, 8.Parsons D.W. Wang T.-L. Samuels Y. Bardelli A. Cummins J.M. DeLong L. Silliman N. Ptak J. Szabo S. Willson J.K.V. Markowitz S. Kinzler K.W. Vogelstein B. Lengauer C. Velculescu V.E. Nature. 2005; 436: 792Crossref PubMed Scopus (491) Google Scholar, 9.Samuels Y. Diaz L.A. 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Cancer PubMed Scopus Google ZKSCAN3 structural features a and unbiased we identified a DNA binding and downstream targets including integrin β4 and ZKSCAN3 is a is that the with ZKSCAN3 K. M. C. K. H. 39: PubMed Scopus Google Scholar), and and with K. M. C. K. H. 39: PubMed Scopus Google Scholar, Y. Y. Yang Z. Wang Y. Z. Wang Z. W. C. Mol. Biol. PubMed Scopus Google Scholar) are also for gene integrin β4 as a direct target and of downstream of ZKSCAN3. expression is in colorectal cancer H. A.B. N. D. Oncogene. 2005; PubMed Scopus Google Scholar) in to ZKSCAN3 as we Integrin β4 as a of cancer and tumor progression Cancer 2005; PubMed Scopus Google Scholar, A. L. Cancer 2005; PubMed Scopus Google Scholar, M. M. Zhang Nature. PubMed Scopus Google Scholar), in and breast cancer, and as a A. L. Cancer 2005; PubMed Scopus Google Scholar) by of to receptor tyrosine A. L. J. Biol. PubMed Scopus Google Scholar, W. Y. A. T. G. Cell. 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PubMed Scopus Google activated with the ZKSCAN3 and the that a phosphatidyl 3-kinase anchorage-independent growth it that this transcription factor this Notwithstanding these to downstream targets with in tumor progression. candidate is with in angiogenesis a for tumor expression with the that the promoter is bound with this zinc finger protein are with the that this gene also a direct ZKSCAN3 target. also by as we in expression of mitogen-activated protein kinase kinase kinase a of expression of this protein Y. S. M. T. M. A. T. T. M. H. J. H. Biol. 2005; PubMed Scopus Google of is induced by ZKSCAN3 this with to in a of colorectal wild type for K-Ras with a Wnt in colorectal cancer are via K-Ras that with the Wnt Y. Zhang 2005; Full Text Full Text PDF PubMed Scopus Google in activated K-Ras and with a Wnt we that ZKSCAN3 is also in a colorectal tumor wild type for this protein and with a Wnt L. T. A. G. 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Nat. PubMed Scopus Google Scholar) were identified as key of breast cancer and and recent studies a mutation for zinc finger transcription factors in breast cancer T. Jones S. Wood L.D. Parsons D.W. Lin J. Barber T. D. Leary R.J. Ptak J. Silliman N. Szabo S. Buckhaults P. C. P. Markowitz S. Willis J. Dawson D. Willson J.K.V. A. Hartigan J. L. C. Parmigiani G. Park B.H. Papadopoulos N. Vogelstein B. Kinzler K.W. Velculescu V.E. Science. PubMed Scopus Google ZKSCAN3 to a short of transcription favoring tumor and we that the underlying mechanism in the of integrin β4 and VEGF, gene previously implicated in colon cancer progression. We and for the of the integrin β4 expression and reporter with
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