FoxM1 Regulates Transcription of JNK1 to Promote the G1/S Transition and Tumor Cell Invasiveness

The Forkhead box M1 (FoxM1) protein is a proliferation-specific transcription factor that plays a key role in controlling both the G1/S and G2/M transitions through the cell cycle and is essential for the development of various cancers. We show here that FoxM1 directly activates the transcription of the c-Jun N-terminal kinase (JNK1) gene in U2OS osteosarcoma cells. Expression of JNK1, which regulates the expression of genes important for the G1/S transition, rescues the G1/S but not the G2/M cell cycle block in FoxM1-deficient cells. Knockdown of either FoxM1 or JNK1 inhibits tumor cell migration, invasion, and anchorage-independent growth. However, expression of JNK1 in FoxM1-depleted cells does not rescue these defects, indicating that JNK1 is a necessary but insufficient downstream mediator of FoxM1 in these processes. Consistent with this interpretation, FoxM1 regulates the expression of the matrix metalloproteinases MMP-2 and MMP-9, which play a role in tumor cell invasion, through JNK1-independent and -dependent mechanisms in U2OS cells, respectively. Taken together, these findings identify JNK1 as a critical transcriptional target of FoxM1 that contributes to FoxM1-regulated cell cycle progression, tumor cell migration, invasiveness, and anchorage-independent growth. The Forkhead box M1 (FoxM1) protein is a proliferation-specific transcription factor that plays a key role in controlling both the G1/S and G2/M transitions through the cell cycle and is essential for the development of various cancers. We show here that FoxM1 directly activates the transcription of the c-Jun N-terminal kinase (JNK1) gene in U2OS osteosarcoma cells. Expression of JNK1, which regulates the expression of genes important for the G1/S transition, rescues the G1/S but not the G2/M cell cycle block in FoxM1-deficient cells. Knockdown of either FoxM1 or JNK1 inhibits tumor cell migration, invasion, and anchorage-independent growth. However, expression of JNK1 in FoxM1-depleted cells does not rescue these defects, indicating that JNK1 is a necessary but insufficient downstream mediator of FoxM1 in these processes. Consistent with this interpretation, FoxM1 regulates the expression of the matrix metalloproteinases MMP-2 and MMP-9, which play a role in tumor cell invasion, through JNK1-independent and -dependent mechanisms in U2OS cells, respectively. Taken together, these findings identify JNK1 as a critical transcriptional target of FoxM1 that contributes to FoxM1-regulated cell cycle progression, tumor cell migration, invasiveness, and anchorage-independent growth. The Forkhead box (Fox) 4The abbreviations used are: Fox, Forkhead box; EMSA, electrophoretic mobility shift assay; JNK, c-Jun N-terminal kinase; ATF-2, activating transcription factor-2; CDKI, cyclin-dependent kinase inhibitors; MEFs, mouse embryonic fibroblasts; MMPs, matrix metalloproteinases; FBS, fetal bovine serum; BrdU, bromodeoxyuridine; siRNA, short interfering RNA; ChIP, chromatin immunoprecipitation assay; qRT-PCR, quantitative real-time RT-PCR; WT, wild type. 4The abbreviations used are: Fox, Forkhead box; EMSA, electrophoretic mobility shift assay; JNK, c-Jun N-terminal kinase; ATF-2, activating transcription factor-2; CDKI, cyclin-dependent kinase inhibitors; MEFs, mouse embryonic fibroblasts; MMPs, matrix metalloproteinases; FBS, fetal bovine serum; BrdU, bromodeoxyuridine; siRNA, short interfering RNA; ChIP, chromatin immunoprecipitation assay; qRT-PCR, quantitative real-time RT-PCR; WT, wild type. family of transcription factors includes more than 50 mammalian members that share sequence homology in the winged helix DNA binding domain (1Kaestner K.H. Knochel W. Martinez D.E. Genes Dev. 2000; 14: 142-146PubMed Google Scholar). The expression of one member of this family, FoxM1, is tightly associated with proliferation and is extinguished in differentiated or resting cells that have exited the cell cycle, suggesting that FoxM1 plays a key role in cell proliferation (2Costa R.H. Nat. Cell Biol. 2005; 7: 108-110Crossref PubMed Scopus (147) Google Scholar). Indeed, the requirement of FoxM1 for cell proliferation has been demonstrated in hepatocytes in vivo, and in endothelial cells and various mesenchymal cell types in vitro (3Wang X. Kiyokawa H. Dennewitz M.B. Costa R.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16881-16886Crossref PubMed Scopus (271) Google Scholar, 4Ye H. Holterman A.X. Yoo K.W. Franks R.R. Costa R.H. Mol. Cell. Biol. 1999; 19: 8570-8580Crossref PubMed Scopus (165) Google Scholar, 5Kalinichenko V.V. Gusarova G.A. Tan Y. Wang I.C. Major M.L. Wang X. Yoder H.M. Costa R.H. J. Biol. Chem. 2003; 278: 37888-37894Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 6Krupczak-Hollis K. Wang X. Kalinichenko V.V. Gusarova G.A. Wang I.C. Dennewitz M.B. Yoder H.M. Kiyokawa H. Kaestner K.H. Costa R.H. Dev. Biol. 2004; 276: 74-88Crossref PubMed Scopus (169) Google Scholar). FoxM1 is highly expressed in many tumor-derived cell lines, and promotes the development of various types of cancers, including hepatocellular carcinoma, prostate cancer, lung cancer, and colorectal cancer in established mouse models (7Kalinichenko V.V. Major M.L. Wang X. Petrovic V. Kuechle J. Yoder H.M. Dennewitz M.B. Shin B. Datta A. Raychaudhuri P. Costa R.H. Genes Dev. 2004; 18: 830-850Crossref PubMed Scopus (322) Google Scholar, 8Kim I.M. Ackerson T. Ramakrishna S. Tretiakova M. Wang I.C. Kalin T.V. Major M.L. Gusarova G.A. Yoder H.M. Costa R.H. Kalinichenko V.V. Cancer Res. 2006; 66: 2153-2161Crossref PubMed Scopus (282) Google Scholar, 9Kalin T.V. Wang I.C. Ackerson T.J. Major M.L. Detrisac C.J. Kalinichenko V.V. Lyubimov A. Costa R.H. Cancer Res. 2006; 66: 1712-1720Crossref PubMed Scopus (239) Google Scholar, 10Yoshida Y. Wang I.C. Yoder H.M. Davidson N.O. Costa R.H. Gastroenterology. 2007; 132: 1420-1431Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 11Wang I.C. Meliton L. Tretiakova M. Costa R.H. Kalinichenko V.V. Kalin T.V. Oncogene. 2008; Google Scholar). In recent studies, FoxM1 has emerged as a critical regulator of both the G1/S and G2/M transitions through the cell cycle (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar, 13Laoukili J. Kooistra M.R. Bras A. Kauw J. Kerkhoven R.M. Morrison A. Clevers H. Medema R.H. Nat. Cell Biol. 2005; 7: 126-136Crossref PubMed Scopus (608) Google Scholar). FoxM1–/– MEFs and human U2OS osteosarcoma cells depleted of FoxM1 by siRNA failed to proliferate in culture because of reduced DNA replication and a block in mitotic progression (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). Using transcription and chromatin immunoprecipitation assays, we and others (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar, 13Laoukili J. Kooistra M.R. Bras A. Kauw J. Kerkhoven R.M. Morrison A. Clevers H. Medema R.H. Nat. Cell Biol. 2005; 7: 126-136Crossref PubMed Scopus (608) Google Scholar, 14Wonsey D.R. Follettie M.T. Cancer Res. 2005; 65: 5181-5189Crossref PubMed Scopus (278) Google Scholar) have shown FoxM1 is directly involved in the transcriptional activation of specific genes that regulate the entry into and progression through mitosis, including Cdc25B, cyclin B, polo-like kinase, aurora B kinase, and centromere protein (CENP)-A, CENP-B, and CENP-F. In addition, FoxM1 is essential for the transcription of Skp2 and Cks1, which encode subunits of the Skp-Cullin 1-F-box (SCF) ubiquitin ligase complex that targets the CDK inhibitor proteins p21Cip1 and p27Kip1 for the G1/S (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar, M. B. K. K. S. Cancer Res. 2006; 66: PubMed Scopus (271) Google Scholar). FoxM1-deficient cells of p21Cip1 and to entry into the V. Costa R.H. Raychaudhuri P. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). The as protein gene family is by and DNA A. M. Google Scholar, Cell Biol. PubMed Scopus Google Scholar). the JNK1 and expressed in cell is specific to cells. of including cell and the Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, Cell 2003; PubMed Google Scholar). activation by or downstream including the transcription factors ATF-2, factor of cells and the activation of gene transcription S. T. J. B. J. PubMed Scopus Google Scholar, Cell Biol. 2007; 19: PubMed Scopus Google Scholar). to the c-Jun N-terminal domain and and to c-Jun activation and with members of the and or and or to to the transcription factors Oncogene. 2003; PubMed Scopus Google Scholar). is to directly genes cyclin cyclin and cyclin which and cell cycle progression through the G1/S J. 1999; 18: PubMed Scopus Google Scholar, P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. 2003; PubMed Scopus Google Scholar, M. H. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). in in to M. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). In this we show that FoxM1 directly activates transcription of JNK1 in U2OS osteosarcoma cells, and both FoxM1 and JNK1 necessary for cell cycle progression, tumor cell migration, invasion, and anchorage-independent growth. Expression of JNK1 rescues the G1/S cell cycle block in FoxM1-depleted cells, indicating that JNK1 as the mediator of FoxM1 in the G1/S FoxM1 regulates the expression of MMP-2 and MMP-9, which is associated with tumor cell and invasion, through JNK1-independent and -dependent respectively. findings identify JNK1 as a transcriptional target of FoxM1 that contributes to FoxM1-regulated G1/S transition, tumor cell migration, invasion, and anchorage-independent growth. Cell and siRNA U2OS osteosarcoma cells and FoxM1–/– MEFs as (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). FoxM1 siRNA and siRNA by and into U2OS cells as I.M. Ackerson T. Ramakrishna S. Tretiakova M. Wang I.C. Kalin T.V. Major M.L. Gusarova G.A. Yoder H.M. Costa R.H. Kalinichenko V.V. Cancer Res. 2006; 66: 2153-2161Crossref PubMed Scopus (282) Google Scholar, I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). U2OS cells or for and and protein of the JNK1 the of the human JNK1 U2OS DNA by the and The with and into and by DNA of JNK1 cells cells in a and with of either expression or of JNK1 and of as and protein to with to as M.L. Costa R.H. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). expressed as of transcription by the expression the with in and with WT, and FoxM1–/– MEFs, MEFs, or U2OS cells and to as (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). The and and used to and the of human by real-time and and and and and mouse the and to human or mouse as (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). in U2OS cells as (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). The used to the human gene with the binding of the transcription and in the or and and and cells FoxM1 siRNA FoxM1–/– MEFs Cell to or mouse Cell as (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). protein U2OS cells and used to a of the human JNK1 that with and kinase as M.L. 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Genes Dev. 2004; 18: 830-850Crossref PubMed Scopus (322) Google Scholar, 9Kalin T.V. Wang I.C. Ackerson T.J. Major M.L. Detrisac C.J. Kalinichenko V.V. Lyubimov A. Costa R.H. Cancer Res. 2006; 66: 1712-1720Crossref PubMed Scopus (239) Google Scholar). The culture fetal or more than 50 cells Cell and by the the cells with or inhibitor for and and into bovine to the cell to the as the cells the with and in in and In cells either with inhibitor or with cells and to into a and cell cells and with of the cells and and the in by the the with Expression of FoxM1 and FoxM1 is to regulate a essential for mitotic progression, the G1/S is not (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). we the expression of FoxM1 in mouse to the cell cycle by In MEFs by the expression of a of X. D. A. K. Kiyokawa H. Genes Dev. 2002; PubMed Scopus Google Scholar, Chen Chen V. A. Kiyokawa H. Cancer Cell. 2006; Full Text Full Text PDF PubMed Scopus Google FoxM1 by The expression of JNK1 suggesting that FoxM1 regulate JNK1 this we the of FoxM1 by of U2OS osteosarcoma cells with but not siRNA, depleted FoxM1 and protein B and Knockdown of FoxM1 in the of JNK1 by not The of which a transcription factor in the of cyclin and cyclin P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. H. A. M. T. T. K. Cell Res. PubMed Scopus Google Scholar, P. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google reduced in cells. Knockdown of FoxM1 the of JNK1 and proteins JNK1 is to and c-Jun and ATF-2, which entry into K. K. A. M. Mol. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Consistent with the JNK1 FoxM1-depleted cells reduced of c-Jun and The expression of cyclin a transcription target of c-Jun M. H. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google by JNK1 expression reduced in FoxM1–/– MEFs with or MEFs with the that FoxM1 regulates JNK1, FoxM1 to reduced JNK1 and of the JNK1 c-Jun and and expression of the c-Jun target gene cyclin FoxM1 the JNK1 FoxM1 into which is the and the in which in the DNA binding and the H. U. L. S. Costa R.H. Mol. Cell. Biol. PubMed Scopus Google Scholar, W. J. Clevers H. Res. 25: PubMed Scopus Google Scholar). We FoxM1 binding H. U. L. S. Costa R.H. Mol. Cell. Biol. PubMed Scopus Google Scholar, M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and and a and of the human JNK1 suggesting the that JNK1 is a transcriptional target of We used to these FoxM1 binding of U2OS cells of the sequence of the JNK1 to a which by the transcriptional of FoxM1 the JNK1 we U2OS cells with a expression and a of the human JNK1 of in in JNK1 of FoxM1 siRNA transcriptional activation of the JNK1 FoxM1 directly to the human JNK1 we to DNA in the of the FoxM1 binding Indeed, that FoxM1 protein is directly to the human JNK1 of FoxM1 by siRNA the binding of FoxM1 and to the JNK1 the by a of transcription of FoxM1 not the of to the We FoxM1 binding and of the human shown by FoxM1 protein is associated with the human that is by siRNA of FoxM1 Taken together, these that FoxM1 directly to the human JNK1 and activates JNK1 FoxM1 the and is for expression and suggesting that FoxM1 regulate as JNK1 for the G1/S have shown that FoxM1 inhibits cell cycle progression both the G1/S and G2/M (12Wang I.C. Chen Y.J. Hughes D. Petrovic V. Major M.L. Park H.J. Tan Y. Ackerson T. Costa R.H. Mol. Cell. Biol. 2005; 25: 10875-10894Crossref PubMed Scopus (484) Google Scholar). FoxM1 is for the of cells into the cell cycle with or U2OS cells in for to cells into a M.L. Costa R.H. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). with and to various the of cells with DNA in and cells to and suggesting that of these cells in the of cells with DNA to the to and indicating the of these cells into the of FoxM1-depleted cells in and the of FoxM1 the progression of cells into we JNK1 expression by FoxM1 is essential for G1/S U2OS cells with or and of FoxM1 or JNK1 by siRNA and or of cells with to in in cell indicating that FoxM1 and JNK1 both critical for cell proliferation the specific role of JNK1, we the of JNK1 in FoxM1-depleted cells of the expression FoxM1-depleted cells a in cells with U2OS cells as by Expression of JNK1 in FoxM1-depleted cells progression, cells to of the in cells with the inhibitor a of cells, the that is for G1/S the that FoxM1-regulated JNK1 expression is critical for G1/S progression we the role of JNK1 in DNA Knockdown of FoxM1 by siRNA or of by both DNA of JNK1 in FoxM1-depleted cells DNA findings that JNK1 expression in FoxM1-depleted cells a block in DNA and G1/S JNK1 expression in FoxM1-deficient cells in a in of G2/M cells with cells and a with FoxM1-depleted cells that expression of JNK1 in FoxM1-depleted cells to the G2/M block by FoxM1 FoxM1 and JNK1 in and of Cancer plays a critical role in tumor and promotes (7Kalinichenko V.V. Major M.L. Wang X. Petrovic V. Kuechle J. Yoder H.M. Dennewitz M.B. Shin B. Datta A. Raychaudhuri P. Costa R.H. Genes Dev. 2004; 18: 830-850Crossref PubMed Scopus (322) Google Scholar, 8Kim I.M. Ackerson T. Ramakrishna S. Tretiakova M. Wang I.C. Kalin T.V. Major M.L. Gusarova G.A. Yoder H.M. Costa R.H. Kalinichenko V.V. Cancer Res. 2006; 66: 2153-2161Crossref PubMed Scopus (282) Google Scholar, M. M. W. M. 2007; 7: PubMed Scopus Google Scholar). FoxM1 and JNK1 in this we the of U2OS cells to in that expression of FoxM1 or Knockdown of FoxM1 by siRNA reduced to of Knockdown of FoxM1 is to in p27Kip1 V. Costa R.H. Raychaudhuri P. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google and of cells with p27Kip1 siRNA in of JNK1 by either or with the inhibitor to of Expression of JNK1 in FoxM1-depleted cells of the failed to rescue in that FoxM1 is a critical regulator of anchorage-independent and JNK1 is a necessary but insufficient downstream target of FoxM1 in this The of tumor cells to and into the critical for the specific of FoxM1 and downstream target JNK1 in we essential for tumor cell and U2OS cells to that expression of FoxM1 or JNK1, and to to in vitro of either FoxM1 or JNK1 by siRNA, or of by the with the or cells Expression of JNK1 in FoxM1-depleted cells not rescue this we the of FoxM1 and JNK1 in the of U2OS tumor cells a of FoxM1 or JNK1 by or of JNK1 by reduced the of U2OS cells through the by Expression of JNK1 in FoxM1-depleted cells not rescue this Taken together, these show that FoxM1 plays essential role in tumor cell migration, invasion, and anchorage-independent with JNK1 a necessary but insufficient downstream mediator of FoxM1 in these in cells depleted of FoxM1 or cells as and through cells with and of cells in The in in cell in cells in as to the of expression of FoxM1, JNK1, and FoxM1 Expression of MMP-9, but through JNK1 in U2OS metalloproteinases in tumor cell and by the In MMP-2 and the of and cells to the we FoxM1 regulate MMP-2 and which to tumor cell of FoxM1 by siRNA MMP-2 and expression in U2OS cells by 50 and indicating that MMP-2 and both by However, of by expression by but MMP-2 expression of JNK1 in FoxM1-depleted cells in a in expression with the but MMP-2 expression that and MMP-2 gene expression is by FoxM1 through and respectively. The findings of this into the by which FoxM1 regulates cell cycle FoxM1 directly activates the transcription of JNK1, which plays essential role in FoxM1 in the G1/S FoxM1 and JNK1 critical for cell migration, invasion, and anchorage-independent in U2OS osteosarcoma cells. in through the expression of and the expression of both by FoxM1 as regulator of the JNK1 to cell cycle progression and tumor cell and We show that of is to the G1/S block by FoxM1 of JNK1 rescues this in FoxM1-depleted cells. findings that the is necessary and for the FoxM1 in G1/S JNK1 protein in FoxM1-depleted cells in reduced and activation of c-Jun B. M. T. B. T. M. Cell. Full Text PDF PubMed Scopus Google Scholar) and B and c-Jun and transcription factors that the expression of genes essential for G1/S progression, including cyclin cyclin and cyclin J. 1999; 18: PubMed Scopus Google Scholar, T. 2003; PubMed Scopus Google Scholar, M. H. J. Biol. 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In established FoxM1 is critical for the development and of hepatocellular prostate cancer, lung cancer, and colorectal cancer (7Kalinichenko V.V. Major M.L. Wang X. Petrovic V. Kuechle J. Yoder H.M. Dennewitz M.B. Shin B. Datta A. Raychaudhuri P. Costa R.H. Genes Dev. 2004; 18: 830-850Crossref PubMed Scopus (322) Google Scholar, 8Kim I.M. Ackerson T. Ramakrishna S. Tretiakova M. Wang I.C. Kalin T.V. Major M.L. Gusarova G.A. Yoder H.M. Costa R.H. Kalinichenko V.V. Cancer Res. 2006; 66: 2153-2161Crossref PubMed Scopus (282) Google Scholar, 9Kalin T.V. Wang I.C. Ackerson T.J. Major M.L. Detrisac C.J. Kalinichenko V.V. Lyubimov A. Costa R.H. Cancer Res. 2006; 66: 1712-1720Crossref PubMed Scopus (239) Google Scholar, 10Yoshida Y. Wang I.C. Yoder H.M. Davidson N.O. Costa R.H. Gastroenterology. 2007; 132: 1420-1431Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). that FoxM1 plays a critical role in tumor development and that FoxM1 tumor M. M. W. 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