Tissue Transglutaminase Regulates Matrix Metalloproteinase-2 in Ovarian Cancer by Modulating cAMP-response Element-binding Protein Activity

Tissue transglutaminase 2 (TG2) is overexpressed in epithelial ovarian cancer (EOC) and promotes intraperitoneal metastasis. How TG2 facilitates the spread of EOC is unknown. Here, we show that TG2 regulates the expression and function of matrix metalloproteinase-2 (MMP-2), a critical mediator of tissue invasiveness. TG2 knockdown down-regulates MMP-2 protein and mRNA expression in SKOV3, IGROV-1, MDA-MB-436, and PC-3 cancer cells. TG2 knockdown or inhibition of TG2 activity using KCC009 decreases MMP-2 gelatinase activity in cancer cells. MMP-2 expression and function are regulated by TG2 at transcriptional level, as demonstrated by quantitative PCR and reporter assays. We used bioinformatics and chromatin immunoprecipitation to identify a CREB binding site in the MMP-2 promoter. Binding of CREB to the MMP-2 promoter was diminished in cells that expressed decreased TG2 levels. TG2 knockdown decreased CREB phosphorylation, and CREB knockdown decreased MMP-2 expression. The effect of TG2 on CREB activity and MMP-2 transcription is mediated by TG2-dependent degradation of protein phosphatase 2 (PP2A-α). We show that PP2A-α complexes with and is targeted for degradation by TG2. In addition to their related in vitro expression levels, TG2 and MMP-2 expression were significantly correlated in vivo, as shown by concordant immunostaining in peritoneal xenografts and in human ovarian tumors. The capacity of TG2 to regulate MMP-2 expression in vitro and in vivo identifies a mechanism that may facilitate tissue invasion and the spread of EOC. The demonstration that TG2 induced degradation of PP2A-α activates CREB, and thereby increases MMP-2 transcription, provides novel mechanistic insight into the pro- metastatic function of TG2. Tissue transglutaminase 2 (TG2) is overexpressed in epithelial ovarian cancer (EOC) and promotes intraperitoneal metastasis. How TG2 facilitates the spread of EOC is unknown. Here, we show that TG2 regulates the expression and function of matrix metalloproteinase-2 (MMP-2), a critical mediator of tissue invasiveness. TG2 knockdown down-regulates MMP-2 protein and mRNA expression in SKOV3, IGROV-1, MDA-MB-436, and PC-3 cancer cells. TG2 knockdown or inhibition of TG2 activity using KCC009 decreases MMP-2 gelatinase activity in cancer cells. MMP-2 expression and function are regulated by TG2 at transcriptional level, as demonstrated by quantitative PCR and reporter assays. We used bioinformatics and chromatin immunoprecipitation to identify a CREB binding site in the MMP-2 promoter. Binding of CREB to the MMP-2 promoter was diminished in cells that expressed decreased TG2 levels. TG2 knockdown decreased CREB phosphorylation, and CREB knockdown decreased MMP-2 expression. The effect of TG2 on CREB activity and MMP-2 transcription is mediated by TG2-dependent degradation of protein phosphatase 2 (PP2A-α). We show that PP2A-α complexes with and is targeted for degradation by TG2. In addition to their related in vitro expression levels, TG2 and MMP-2 expression were significantly correlated in vivo, as shown by concordant immunostaining in peritoneal xenografts and in human ovarian tumors. The capacity of TG2 to regulate MMP-2 expression in vitro and in vivo identifies a mechanism that may facilitate tissue invasion and the spread of EOC. The demonstration that TG2 induced degradation of PP2A-α activates CREB, and thereby increases MMP-2 transcription, provides novel mechanistic insight into the pro- metastatic function of TG2. Transglutaminase 2 (TG2), 2The abbreviations used are:TG2transglutaminase 2EOCepithelial ovarian cancerMMPmatrix metalloproteinaseMAPKmitogen-activated protein kinaseCREBcAMP-response element-binding proteinGAPDHglyceraldehyde-3-phosphate dehydrogenasesiRNAsmall interference RNAChIPchromatin immunoprecipitationIHCimmunohistochemistryPP2A-αprotein phosphatase 2. an enzyme overexpressed in epithelial malignancies (1.Satpathy M. Cao L. Pincheira R. Emerson R. Bigsby R. Nakshatri H. Matei D. Cancer Res. 2007; 67: 7194-7202Crossref PubMed Scopus (91) Google Scholar, 2.Mann A.P. Verma A. Sethi G. Manavathi B. Wang H. Fok J.Y. Kunnumakkara A.B. Kumar R. Aggarwal B.B. Mehta K. Cancer Res. 2006; 66: 8788-8795Crossref PubMed Scopus (178) Google Scholar), cross-links proteins by acyl-transfer between glutamine and lysine residues and participates in Ca2+-dependent post-translational protein modification by incorporating polyamines into peptide chains (3.Pincus J.H. Waelsch H. Arch. Biochem. Biophys. 1968; 126: 44-52Crossref PubMed Scopus (42) Google Scholar). We recently reported that TG2 is up-regulated in transformed ovarian epithelial cells and tumors compared with normal cells, and facilitates peritoneal dissemination of EOC cells (1.Satpathy M. Cao L. Pincheira R. Emerson R. Bigsby R. Nakshatri H. Matei D. Cancer Res. 2007; 67: 7194-7202Crossref PubMed Scopus (91) Google Scholar, 4.Matei D. Graeber T.G. Baldwin R.L. Karlan B.Y. Rao J. Chang D.D. Oncogene. 2002; 21: 6289-6298Crossref PubMed Scopus (89) Google Scholar). TG2 has multiple functions. It strengthens integrin-dependent cell adhesion, modulates intracellular signaling, and remodels the extracellular matrix through protein cross-linking (5.Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar). To understand the involvement of TG2 in the process of intraperitoneal metastasis, we investigated its involvement in the regulation of proteins known to facilitate tumor invasion and spread. transglutaminase 2 epithelial ovarian cancer matrix metalloproteinase mitogen-activated protein kinase cAMP-response element-binding protein glyceraldehyde-3-phosphate dehydrogenase small interference RNA chromatin immunoprecipitation immunohistochemistry protein phosphatase 2. Matrix metalloproteinases (MMPs) are a family of secreted proteins that remodel and digest the extracellular matrix. In the context of malignancy, MMPs play a prominent role in metastasis and angiogenesis (6.Bergers G. Brekken R. McMahon G. Vu T.H. Itoh T. Tamaki K. Tanzawa K. Thorpe P. Itohara S. Werb Z. Hanahan D. Nat. Cell Biol. 2000; 2: 737-744Crossref PubMed Scopus (2284) Google Scholar), because degradation of the extracellular matrix in the immediate vicinity of a tumor niche facilitates cancer cell invasion and escape from the primary tumor site (7.Himelstein B.P. Canete-Soler R. Bernhard E.J. Dilks D.W. Muschel R.J. Invasion Metastasis. 1994; 14: 246-258PubMed Google Scholar, 8.Hanahan D. Lanzavecchia A. Mihich E. Cancer Res. 2003; 63: 3005-3008PubMed Google Scholar). Regulation of MMP activity occurs at different levels (9.Overall C.M. Lopez-Otin C. Nat. Rev. Cancer. 2002; 2: 657-672Crossref PubMed Scopus (1135) Google Scholar). MMPs are secreted as pro-zymogens that require processing to active proteases. Proteolytic activation of pro-MMPs requires removal of an auto-inhibitory pro-peptide domain and is accomplished by plasminogen, trypsin, kallikrein, or membrane type-1 MMP (10.Van den Steen P.E. Dubois B. Nelissen I. Rudd P.M. Dwek R.A. Opdenakker G. Crit. Rev. Biochem. Mol. Biol. 2002; 37: 375-536Crossref PubMed Scopus (745) Google Scholar). Tissue inhibitors of metalloproteinases are physiological inhibitors of MMP activities (11.Davidson B. Reich R. Risberg B. Nesland J.M. Arkh. Patol. 2002; 64: 47-53PubMed Google Scholar). Expression of tissue inhibitors of metalloproteinases correlates inversely with tumor invasiveness and MMP activity (12.Moran A. Iniesta P. Garcia-Aranda C. De Juan C. Diaz-Lopez A. Sanchez-Pernaute A. Torres A.J. Diaz-Rubio E. Balibrea J.L. Benito M. Oncol. Rep. 2005; 13: 115-120PubMed Google Scholar). In pathological states, such as malignancy, up-regulated MMP activity may be due to increased expression caused by abnormal transcription (13.Benbow U. Brinckerhoff C.E. Matrix Biol. 1997; 15: 519-526Crossref PubMed Scopus (443) Google Scholar). MMP promoters harbor several cis-elements that can be transactivated by a number of transcription factors, including AP-1, Sp-1, PEA3, NF-κB, and others. Interestingly, the structures of different MMP promoters are similar, allowing coordinated regulation of these proteases in specific tissues, with MMP-1, -3, -9, -10, -12, and -13 being regulated by AP-1-responsive elements (13.Benbow U. Brinckerhoff C.E. Matrix Biol. 1997; 15: 519-526Crossref PubMed Scopus (443) Google Scholar), whereas MMP-2, -14, and -28 are Sp-1-responsive (14.Kuo L. Chang H.C. Leu T.H. Maa M.C. Hung W.C. J. Cell Physiol. 2006; 207: 729-734Crossref PubMed Scopus (69) Google Scholar, 15.Lohi J. Lehti K. Valtanen H. Parks W.C. Keski-Oja J. Gene (Amst.). 2000; 242: 75-86Crossref PubMed Scopus (115) Google Scholar). Unlike the MMP-9 family that is regulated by growth factors and cytokines upstream of MAPK/FAK signaling or inflammatory pathways that converge on NF-κB, the MMP-2 group of metalloproteinases is less responsive to extracellular stimuli and is expressed constitutively in tissues. The MMPs, particularly MMP-1, -2, and -9, are expressed abundantly in EOC cells (16.Sillanpaa S. Anttila M. Voutilainen K. Ropponen K. Turpeenniemi-Hujanen T. Puistola U. Tammi R. Tammi M. Sironen R. Saarikoski S. Kosma V.M. Gynecol. Oncol. 2007; 104: 296-303Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 17.Smolarz B. Szyllo K. Romanowicz-Makowska H. Niewiadomski M. Kozlowska E. Kulig A. Pol. J. Pathol. 2003; 54: 233-238PubMed Google Scholar, 18.Stadlmann S. Pollheimer J. Moser P.L. Raggi A. Amberger A. Margreiter R. Offner F.A. Mikuz G. Dirnhofer S. Moch H. Eur. J. Cancer. 2003; 39: 2499-2505Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 19.Szyllo K. Smolarz B. Romanowicz-Makowska H. Niewiadomski M. Kozlowska E. Kulig A. J. Exp. Clin. Cancer Res. 2002; 21: 357-361PubMed Google Scholar, 20.Westerlund A. Hujanen E. Puistola U. Turpeenniemi-Hujanen T. Gynecol. Oncol. 1997; 67: 76-82Abstract Full Text PDF PubMed Scopus (27) Google Scholar). MMP-2, also known as gelatinase A, is overexpressed in ovarian tumors and secreted in ascites fluid (20.Westerlund A. Hujanen E. Puistola U. Turpeenniemi-Hujanen T. Gynecol. Oncol. 1997; 67: 76-82Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 21.Schmalfeldt B. Prechtel D. Harting K. Spathe K. Rutke S. Konik E. Fridman R. Berger U. Schmitt M. Kuhn W. Lengyel E. Clin. Cancer Res. 2001; 7: 2396-2404PubMed Google Scholar), and its activity correlates with clinical outcome (22.Perigny M. I. I. M. M. B. J. Clin. Pathol. PubMed Scopus Google Scholar). of MMP-2 by transformed ovarian epithelial cells is a critical in the process of peritoneal the of EOC cells to the peritoneal through of and in the extracellular S. Lengyel E. J. Clin. PubMed Scopus Google Scholar). MMP-2 regulation in EOC their in the extracellular TG2 as a and MMP-2 as a we that a regulated between TG2 and MMP-2 may in the tumor the proteins regulate we that tissue transglutaminase regulates the expression of expression of TG2 and MMP-2 was in cancer cell ovarian and We show that in ovarian cancer cells TG2 modulates cAMP-response element-binding protein activation and the expression of MMP-2 in a The of TG2 on CREB activity are due to its the PP2A-α phosphatase for a to TG2 in metastasis and a role for TG2 in the that TG2 may be an in ovarian cancer metastasis. TG2 and MMP-2 were from to CREB, and were from Cell was from and were from were from and human MMP-2 was from and human TG2 was from The TG2 KCC009 was by The human cancer cell SKOV3, and PC-3 were from the The cell was a from L. and cells were in growth and with and and IGROV-1, and PC-3 cells were in and were at To an into was into cells using cells were with The was a from of J. M. 2001; PubMed Scopus Google Scholar). was in cells, as by protein expression. were by with of TG2 was demonstrated by To human TG2 in the was into and ovarian cancer cells that TG2. The the was in were and TG2 was by of RNA was with TG2 CREB and PP2A-α Cell was used as was used for were into a inhibitors and were and to and were using and of protein were by and were with primary at with a complexes were using were by a with a was with were on into and were to of protein from the was at with of or with of for at complexes were in for in protein and used for as tumor metastasis was from The expression of that or tumor metastasis and as The compared expression in ovarian cancer cells with or RNA from cell was and the was The was and was in to with at were to was used for was to cells. The was for and and at for to of were on with 2 were with to and and in at to by was used for in MMP activity was as the of the were with a and the of was using the processing of and PCR were used to MMP-2 and PP2A-α expression in or cells. RNA from the cells using RNA was in a of using the MMP-2, and and and and The and were at for by of for and for MMP-2 at at and at and PP2A-α at at and at by a of at The was on a PCR we used the on an to the specific for MMP-2 were and and specific for were and and as the of the PCR a was and the was for the and for expression of MMP-2 was as by the of the from that of the are as of was in and in at To the between CREB and the MMP-2 we used a In cells with or were for in into and on The chromatin was by with of the was used as a and the was with or a CREB complexes were with protein with 2 and and with of complexes was by with at for and was with The was with and to PCR using for the CREB binding domain of the MMP-2 and The PCR were by by and with the a with CREB was using for the promoter and a known CREB a with CREB was with for the MMP-2 upstream of the CREB binding the were and in with from the and the was as was in and with of the CREB binding site from the MMP-2 promoter was with the The at was and the of the promoter was MMP-2 activity was as the to a In was with a known MMP-2 or TG2 for at in and addition of the of the peptide was at an of and of in a tumors intraperitoneal of and cells into were and by immunohistochemistry cell were by a from including human epithelial ovarian tumors in was for MMP-2 and TG2. for TG2 was as (1.Satpathy M. Cao L. Pincheira R. Emerson R. Bigsby R. Nakshatri H. Matei D. Cancer Res. 2007; 67: 7194-7202Crossref PubMed Scopus (91) Google Scholar). To MMP-2, we used a at of and the with a to the of the CREB and MMP-2 promoter activity in and cells. In cells were with Pincheira R. J. Physiol. Cell Physiol. PubMed Scopus Google or an MMP-2 promoter with at a of using The MMP-2 reporter was a from of of H. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). was using a were in and To for for were to are expressed as the The was compared of PCR and activity assays. We used to TG2 expression to CREB in To TG2 to MMP-2 in human tumor the of was at To in between tumors from and cells, we used the at the of demonstrated that TG2 is overexpressed in EOC and intraperitoneal tumor dissemination (1.Satpathy M. Cao L. Pincheira R. Emerson R. Bigsby R. Nakshatri H. Matei D. Cancer Res. 2007; 67: 7194-7202Crossref PubMed Scopus (91) Google Scholar), we TG2 expression is correlated with that of that function in metastasis. We used cells with or a and the metastasis in identify several with expression in compared with cells. In cells with decreased expression of we diminished expression of MMP-2, cancer metastasis and and others. MMP-2 is a critical mediator of metastasis in EOC S. Lengyel E. J. Clin. PubMed Scopus Google Scholar), we on regulation of We MMP-2 protein expression in and cells of MMP-2 expression was in of cells. MMP-2 is a secreted to its expression in by cells significantly less MMP-2 protein by cells We effect in ovarian cancer cell IGROV-1, in TG2 expression was using We decreased expression of MMP-2 in cells with compared with cells with To TG2 MMP-2 we compared MMP-2 activity in by or cells by using activity was in for by cells compared with cells in was for that MMP-2 gelatinase activity is in by cells a to We TG2 regulates MMP-2 expression in cancer cell including cancer cells, and PC-3 cancer cells. TG2 knockdown in these cells was by of MMP-2 expression and activity was in cells in TG2 was compared with MMP-2 expression was diminished in PC-3 cells with compared with show that TG2 regulates MMP-2 expression and activity in ovarian and cancer cell that MMP-2 expression and activity with the expression of we TG2 activates MMP-2 in a TG2 was for with MMP-2 in the of a gelatinase and MMP-2 activity was on of a a known of MMP-2, was used as for the show that TG2 MMP-2 in vitro and that the of TG2 on gelatinase are To the activity of TG2 a role in MMP-2 expression and we used a TG2 L. K. C. R. Mol. Cancer 2005; PubMed Scopus Google Scholar). of ovarian cancer cells with KCC009 decreased the expression and gelatinase activity of MMP-2, that the activity of TG2 is in the expression and activity of To understand the mechanism through TG2 MMP-2 we TG2 the expression of MMP-2 PCR that the of MMP-2 mRNA was diminished in compared with cells PCR a of between the MMP-2 mRNA in cells compared with cells reporter in and cells were with an reporter that MMP-2 promoter activity was decreased by of TG2 that TG2 regulates MMP-2 at the transcriptional CREB has in the transcriptional regulation of MMP-2 in cells M. J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). We the MMP-2 using promoter and a CREB at to in the MMP-2 promoter to CREB the effect of TG2 on MMP-2 in ovarian cancer cells. To we CREB using and that diminished CREB expression was with a in the expression of MMP-2 a we that a CREB the to MMP-2 promoter in cells that CREB modulates MMP-2 transcription in ovarian cancer cells. To the of CREB binding to the MMP-2 promoter in the of MMP-2 transcription, the at was We the capacity of and MMP-2 to an MMP-2 reporter promoter activation was diminished by of the CREB binding site from the MMP-2 promoter that the CREB binding in the MMP-2 promoter is we the expression and activity of TG2 these CREB at was compared in and cells using an that CREB on and on as these are of CREB and was diminished in of compared with cells and to a in of compared with cells The expression of CREB was in and cells To the role of transglutaminase activity in CREB we CREB in cells with the TG2 CREB expression of CREB was by that TG2 is to CREB We the activity of CREB is by the or of TG2. reporter in or the cells, were with a promoter that CREB transcriptional activity was decreased in cells compared with cells inhibition of TG2 with KCC009 decreased CREB transcriptional activity To to MMP-2 transcription is by TG2-dependent CREB we used a to binding of CREB to the MMP-2 promoter in or cells. PCR of the MMP-2 promoter in the chromatin by a CREB was in compared with cells of MMP-2 promoter were chromatin from these cells was to PCR and The of CREB binding to the MMP-2 promoter is shown by the of to the PCR and PCR demonstrated a in of the MMP-2 promoter by the CREB show in ovarian cancer cells, CREB activity is by TG2 and MMP-2 expression and We investigated TG2 participates in CREB CREB on the activities of that CREB and that in CREB including M. S. Mol. Cell Biol. 1994; 14: PubMed Scopus Google Scholar), S. R.L. Mol. Cell Biol. 13: PubMed Scopus Google Scholar, R. K. E. S. G. T. L. P. Exp. Cell Res. 2002; PubMed Scopus Google Scholar, J. J. J. Res. PubMed Scopus Google Scholar), and H. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). To TG2 phosphatase activity and CREB phosphorylation, we and cells with a phosphatase CREB was in of cells compared with cells. of cells with CREB phosphorylation, that are in CREB activation by TG2 at To modulates CREB phosphorylation, we the of using CREB in was diminished in cells of PP2A-α that PP2A-α CREB in ovarian cancer cells. We investigated the effect of TG2 on PP2A-α by its expression in and cells. of TG2 increased PP2A-α expression whereas of human TG2 in or cells diminished We TG2 with We PP2A-α in TG2 and TG2 in PP2A-α that TG2 and PP2A-α are in ovarian cancer cells. We that TG2 may on and the expression of of cells with the TG2 KCC009 increased the expression of that TG2 PP2A-α expression The function of TG2 is to proteins that may be targeted for To PP2A-α is such a TG2 we its in cells or levels of TG2 with In cells TG2 levels, PP2A-α expression in cells, PP2A-α In PP2A-α mRNA was in and cells, the that TG2 PP2A-α that TG2 increases CREB activity by degradation of and transcription of MMP-2 We that intraperitoneal of with cells with diminished TG2 expression to decreased peritoneal dissemination (1.Satpathy M. Cao L. Pincheira R. Emerson R. Bigsby R. Nakshatri H. Matei D. Cancer Res. 2007; 67: 7194-7202Crossref PubMed Scopus (91) Google Scholar). we the of TG2 on MMP-2 in vivo by using that the of TG2 on MMP-2 expression with metastasis. We decreased expression of MMP-2 in xenografts from cells compared with cells of tumors MMP-2 whereas tumors from cells MMP-2 diminished expression of TG2 and MMP-2 was also in of cells from compared with xenografts We also human ovarian tumors on a to to TG2 and MMP-2 was in and of the and the of was to a in vivo between TG2 and We that TG2 is overexpressed in ovarian tumors and a role in peritoneal dissemination (1.Satpathy M. Cao L. Pincheira R. Emerson R. Bigsby R. Nakshatri H. Matei D. Cancer Res. 2007; 67: 7194-7202Crossref PubMed Scopus (91) Google Scholar). The provides insight into TG2 facilitates the spread of ovarian We show that TG2 regulates MMP-2 expression in cancer cells and in human ovarian tumors. We that TG2 the expression of MMP-2 in cancer cells, in human ovarian and in xenografts from cancer cells. The effect of TG2 on MMP-2 and MMP-2 is mediated by the capacity of TG2 to We identify PP2A-α as a phosphatase that CREB We also show that PP2A-α is a of a that TG2 and that the of TG2 and PP2A-α is as TG2 degradation of is the TG2 in the regulation of MMP-2 expression and is also the to show that TG2 regulates CREB phosphorylation, through an effect on a in ovarian cancer cells. of these is that TG2 the transcription and expression of proteins to the spread of including The of TG2 and MMP-2 expression levels is because the proteins in the extracellular TG2 cross-links proteins in the extracellular MMPs the matrix through their Interestingly, MMPs cell thereby cell and on J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). MMP-2, in with MMPs, cell TG2 in cells and its function J. S. PubMed Scopus Google Scholar). The proteins to with the site in to the TG2 may the effect of MMP-2 on the function of transglutaminase J. S. PubMed Scopus Google Scholar). In the we the We show that TG2 regulates the expression and function of MMP-2 in cancer cells and tumors. the of a between that and that the extracellular matrix. Regulation of MMP-2 by TG2 is transcriptional and mediated by CREB is an expressed transcription to the that regulates the expression of in to S. H. J.M. J.M. S. G. Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. Sci. U. S. A. PubMed Scopus Google Scholar). CREB is and is at by protein kinase A, and by growth factors or M. PubMed Scopus Google Scholar, 1994; PubMed Scopus Google Scholar, K. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). CREB at increases its transcriptional activity M. K. T. W. C. K. M. P. J. 1997; PubMed Scopus Google Scholar), by its with proteins that the transcriptional TG2 activates CREB in to their the mechanism was J. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). It was that TG2 modulates the activity of by its and to increased and CREB activity J. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). we show that TG2 expression and function CREB and in ovarian cancer cells and that the TG2 the transcription To is the that a transglutaminase CREB in cancer cells. CREB regulates the transcription of mechanism may be in the of TG2 inhibitors L. K. C. R. Mol. Cancer 2005; PubMed Scopus Google Scholar, K. M. J.L. L. E. P. B. C. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). CREB in the regulation of MMP-2 in ovarian cancer cells are with in a on CREB as a of MMP-2 expression in to M. J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). significantly to by that TG2 activates CREB by the degradation of We an effect of TG2 on expression of the and were to TG2 and that TG2 specific as a TG2 in cancer cells A. S. Wang H. Fok J.Y. D. J. Mehta K. Clin. Cancer Res. 14: PubMed Scopus Google Scholar). with that TG2 proteins with tumor particularly for identify a mechanism through TG2 modulates expression and promotes the spread of ovarian the degradation of and thereby CREB, TG2 to the transcriptional regulation of of the of the capacity of TG2 to through CREB by PP2A-α and tumor proteins to of expression is to insight into that cancer and such as is a the of targeted cancer We and for for with and Nakshatri for of the and and for the TG2 with