Tissue transglutaminase regulates matrix metalloproteinase-2 in ovarian cancer by modulating cAMP-response element-binding protein activity

Minati Satpathy, Minghai Shao, Robert Emerson, David B. Donner, Daniela Matei

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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 prometastatic function of TG2.

Original languageEnglish
Pages (from-to)15390-15399
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number23
DOIs
StatePublished - Jun 5 2009

Fingerprint

Cyclic AMP Response Element-Binding Protein
Matrix Metalloproteinase 2
Ovarian Neoplasms
transglutaminase 2
Transcription
Degradation
Cells
Tissue
Protein Phosphatase 2
Gelatinases
Neoplasms
Phosphorylation
Chromatin Immunoprecipitation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Tissue transglutaminase regulates matrix metalloproteinase-2 in ovarian cancer by modulating cAMP-response element-binding protein activity. / Satpathy, Minati; Shao, Minghai; Emerson, Robert; Donner, David B.; Matei, Daniela.

In: Journal of Biological Chemistry, Vol. 284, No. 23, 05.06.2009, p. 15390-15399.

Research output: Contribution to journalArticle

@article{15b4f707c48242afa18d9d87557d38f9,
title = "Tissue transglutaminase regulates matrix metalloproteinase-2 in ovarian cancer by modulating cAMP-response element-binding protein activity",
abstract = "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 prometastatic function of TG2.",
author = "Minati Satpathy and Minghai Shao and Robert Emerson and Donner, {David B.} and Daniela Matei",
year = "2009",
month = "6",
day = "5",
doi = "10.1074/jbc.M808331200",
language = "English",
volume = "284",
pages = "15390--15399",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "23",

}

TY - JOUR

T1 - Tissue transglutaminase regulates matrix metalloproteinase-2 in ovarian cancer by modulating cAMP-response element-binding protein activity

AU - Satpathy, Minati

AU - Shao, Minghai

AU - Emerson, Robert

AU - Donner, David B.

AU - Matei, Daniela

PY - 2009/6/5

Y1 - 2009/6/5

N2 - 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 prometastatic function of TG2.

AB - 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 prometastatic function of TG2.

UR - http://www.scopus.com/inward/record.url?scp=67650179228&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650179228&partnerID=8YFLogxK

U2 - 10.1074/jbc.M808331200

DO - 10.1074/jbc.M808331200

M3 - Article

C2 - 19324884

AN - SCOPUS:67650179228

VL - 284

SP - 15390

EP - 15399

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 23

ER -