The Experts below are selected from a list of 37731 Experts worldwide ranked by ideXlab platform
Agnès Rötig - One of the best experts on this subject based on the ideXlab platform.
-
twinkle helicase PEO1 gene mutation causes mitochondrial dna depletion
Annals of Neurology, 2007Co-Authors: Emmanuelle Sarzi, Steffi Goffart, Valérie Serre, Dominique Chretien, A. Slama, Arnold Munnich, Johannes N. Spelbrink, Agnès RötigAbstract:Objective Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically and genetically heterogeneous group of autosomal recessive diseases characterized by a reduction in mtDNA copy number. Several nuclear genes have been shown to account for these severe oxidative phosphorylation disorders, but the disease-causing mutations remain largely unknown. Methods By virtue of homozygosity mapping, we tested candidate genes involved in mtDNA maintenance in patients born to consanguineous parents. Results We found homozygosity for microsatellite markers flanking the PEO1 gene, encoding the mitochondrial Twinkle helicase, in two sibs presenting a hepatocerebral form of MDS. Sequencing the PEO1 gene showed a homozygous mutation at a conserved position of the protein in the two patients (T457I). The modeling of the Twinkle protein showed that T457 is located in the interface between two monomers of the hexameric enzyme. Finally, using purified recombinant protein, we demonstrated that the T457I mutant Twinkle has a defective helicase activity. Interpretation Although dominant Twinkle mutations have been previously reported in patients with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions, we report here the first recessive Twinkle mutation in patients with hepatocerebral form of MDS. Identifying other Twinkle mutations in MDS and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on the isolated proteins should help in understanding why some mutations are recessive and others are dominant. Ann Neurol 2007
-
Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.
Annals of neurology, 2007Co-Authors: Emmanuelle Sarzi, Steffi Goffart, Valérie Serre, Dominique Chretien, A. Slama, Arnold Munnich, Johannes N. Spelbrink, Agnès RötigAbstract:Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically and genetically heterogeneous group of autosomal recessive diseases characterized by a reduction in mtDNA copy number. Several nuclear genes have been shown to account for these severe oxidative phosphorylation disorders, but the disease-causing mutations remain largely unknown. By virtue of homozygosity mapping, we tested candidate genes involved in mtDNA maintenance in patients born to consanguineous parents. We found homozygosity for microsatellite markers flanking the PEO1 gene, encoding the mitochondrial Twinkle helicase, in two sibs presenting a hepatocerebral form of MDS. Sequencing the PEO1 gene showed a homozygous mutation at a conserved position of the protein in the two patients (T457I). The modeling of the Twinkle protein showed that T457 is located in the interface between two monomers of the hexameric enzyme. Finally, using purified recombinant protein, we demonstrated that the T457I mutant Twinkle has a defective helicase activity. Although dominant Twinkle mutations have been previously reported in patients with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions, we report here the first recessive Twinkle mutation in patients with hepatocerebral form of MDS. Identifying other Twinkle mutations in MDS and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on the isolated proteins should help in understanding why some mutations are recessive and others are dominant.
Simon P. Langdon - One of the best experts on this subject based on the ideXlab platform.
-
The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer.
Oncotarget, 2015Co-Authors: Rui Huang, Simon P. Langdon, Peter Mullen, Dana Faratian, Matthew Tse, David J. HarrisonAbstract:Chromatin undergoes structural changes in response to extracellular and environmental signals. We observed changes in nuclear morphology in cancer tissue biopsied after chemotherapy and hypothesised that these DNA damage-induced changes are mediated by histone deacetylases (HDACs). Nuclear morphological changes in cell lines (PE01 and PE04 models) and a xenograft model (OV1002) were measured in response to platinum chemotherapy by image analysis of nuclear texture. HDAC2 expression increased in PEO1 cells treated with cisplatin at 24h, which was accompanied by increased expression of heterochromatin protein 1 (HP1). HDAC2 and HP1 expression were also increased after carboplatin treatment in the OV1002 carboplatin-sensitive xenograft model but not in the insensitive HOX424 model. Expression of DNA damage response pathways (pBRCA1, γH2AX, pATM, pATR) showed time-dependent changes after cisplatin treatment. HDAC2 knockdown by siRNA reduced HP1 expression, induced DNA double strand breaks (DSB) measured by γH2AX, and interfered with the activation of DNA damage response induced by cisplatin. Furthermore, HDAC2 depletion affected γH2AX foci formation, cell cycle distribution, and apoptosis triggered by cisplatin, and was additive to the inhibitory effect of cisplatin in cell lines. By inhibiting expression of HDAC2, reversible alterations in chromatin patterns during cisplatin treatment were observed. These results demonstrate quantifiable alterations in nuclear morphology after chemotherapy, and implicate HDAC2 in higher order chromatin changes and cellular DNA damage responses in ovarian cancer cells in vitro and in vivo.
-
Abstract 4085: The roles of HDACs in chromatin remodelling and response to chemotherapy in cancer
Molecular and Cellular Biology, 2012Co-Authors: Rui Huang, Simon P. Langdon, David J. Harrison, Dana FaratianAbstract:Background: Chromatin is dynamic in higher-order structure in response to extracellular and environmental signals. We observed nuclear morphological changes in clinical cancer tissues after chemotherapy. Since chromatin structure dictates gene expression, and therefore function, further investigation of this phenomenon may help us to better understand therapeutic responses. We hypothesise that nuclear morphological changes in cancer in response to DNA-damage by chemotherapy are mediated by histone deacetylases (HDACs). Methods: Ovarian cancer cell lines PEO1/PEO4 (platinum sensitive/resistant) were selected as in vitro models, and primary ovarian cancer xenografts OV1002 and HOX424 as in vivo models. Expression levels of HDACs and heterochromatin protein 1 (HP1) were screened by reverse phase protein array (RPPA) and western blot after treatment with cisplatin. Immunofluorescence imaging was undertaken using confocal microscopy and nuclear texture was measured in Image J using GLCM texture analysis plugin. 38 ovarian cancer patient and 175 xenograft samples were assessed for HDAC and HP1 expression in response to chemotherapy by quantitative immunofluorescence. HDAC2 expression was modulated by interfering RNAs (siRNA). Results: We demonstrate nuclear morphological changes in clinical tumours, xenografts, and cell lines in response to platinum chemotherapy. HDACs and HP1 isoforms showed differential expression in a panel of 25 ovarian cancer cell lines associated with response to chemotherapy with increased expression in treated or resistant lines. Expression of HDACs increased in PEO1 cells treated with cisplatin in a time-dependent fashion. This was accompanied by quantifiable changes in nuclear texture (increased heterogeneity), and high expression of HP1s at early time point (4-24h). The proliferation of PEO1 cells was inhibited and HP1 protein expression decreased after HDAC2 knockdown. In clinical specimens, HDAC8 and HP1 gamma expression significantly increased after chemotherapy, and class I HDAC (1, 2, and 8) and HP1 expression were increased after carboplatin treatment in carboplatin-sensitive xenografts. Chromatin conformation, DNA damage response, and cell cycle progression showed sequential changes over time with carboplatin treatment. Conclusion: These results demonstrate alterations in chromatin structure after chemotherapy, and implicate the role of class I HDACs in higher order chromatin changes and the DNA damage response in ovarian cancer in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4085. doi:1538-7445.AM2012-4085
-
The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer.
The Journal of pathology, 2012Co-Authors: Susanna L. Cooke, Simon P. Langdon, Kevin L. Howe, Scott Newman, Jian Xian, Jillian Temple, Elizabeth M. Batty, Jessica C.m. Pole, Paul A.w. EdwardsAbstract:High-grade serous ovarian carcinoma (HGSOC) is characterized by genomic instability, ubiquitous TP53 loss, and frequent development of platinum resistance. Loss of homologous recombination (HR) is a mutator phenotype present in 50% of HGSOCs and confers hypersensitivity to platinum treatment. We asked which other mutator phenotypes are present in HGSOC and how they drive the emergence of platinum resistance. We performed whole-genome paired-end sequencing on a model of two HGSOC cases, each consisting of a pair of cell lines established before and after clinical resistance emerged, to describe their structural variants (SVs) and to infer their ancestral genomes as the SVs present within each pair. The first case (PEO1/PEO4), with HR deficiency, acquired translocations and small deletions through its early evolution, but a revertant BRCA2 mutation restoring HR function in the resistant lineage re-stabilized its genome and reduced platinum sensitivity. The second case (PEO14/PEO23) had 216 tandem duplications and did not show evidence of HR or mismatch repair deficiency. By comparing the cell lines to the tissues from which they originated, we showed that the tandem duplicator mutator phenotype arose early in progression in vivo and persisted throughout evolution in vivo and in vitro, which may have enabled continual evolution. From the analysis of SNP array data from 454 HGSOC cases in The Cancer Genome Atlas series, we estimate that 12.8% of cases show patterns of aberrations similar to the tandem duplicator, and this phenotype is mutually exclusive with BRCA1/2 carrier mutations.
-
Functional Restoration of BRCA2 Protein by Secondary BRCA2 Mutations in BRCA2-Mutated Ovarian Carcinoma
Cancer research, 2009Co-Authors: Wataru Sakai, Simon P. Langdon, Elizabeth M. Swisher, Céline Jacquemont, Kurapaty Venkatapoorna Chandramohan, Fergus J. Couch, Kaitlyn Wurz, Jake Higgins, Emily Villegas, Toshiyasu TaniguchiAbstract:Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, the mechanism of the drug resistance has not been elucidated. Here, we show functional significance of restoration of BRCA2 protein by secondary BRCA2 mutations in acquired drug resistance of BRCA2-mutated ovarian carcinoma. Three ovarian cancer cell lines (PEO1, PEO4, and PEO6) were derived from a BRCA2 mutation [5193C>G (Y1655X)] carrier with ovarian carcinoma with acquired cisplatin resistance and a secondary BRCA2 mutation [5193C>T (Y1655Y)] that canceled the inherited mutation. PEO1 was BRCA2 deficient and sensitive to cisplatin and a poly(ADP-ribose) polymerase inhibitor, AG14361, whereas PEO4 was resistant. PEO4 and PEO6, derived from ascites at the time of relapse with cisplatin resistance, had the secondary mutation and were BRCA2 proficient. In vitro cisplatin/AG14361 selection of PEO1 led to restoration of BRCA2 due to another secondary BRCA2 mutation. BRCA2 depletion sensitized BRCA2-restored PEO1 clones and PEO4 to cisplatin/AG14361. Thus, restoration of BRCA2 due to secondary BRCA2 mutation is involved in acquired drug resistance of BRCA2-mutated ovarian carcinoma.
-
Effect of matrigel on the tumorigenicity of human breast and ovarian carcinoma cell lines
International journal of cancer, 1996Co-Authors: Peter Mullen, Simon P. Langdon, Alison Ritchie, William R. MillerAbstract:The effect of Matrigel, a solubilised tissue basement membrane extract, has been investigated on the tumorigenicity of 3 breast (MCF-7, T47D and MDA.MB.231) and 5 ovarian [PEO1, PEO1 cDDPr, PEO4, PEO14 and OV(hyg)CAR3] carcinoma cell lines. In the absence of Matrigel, the PEO14 and MDA.MB.231 cell lines produced take rates of 30% and 50%, respectively, while the other cell lines either did not develop or only occasionally developed as tumours. With Matrigel, 100% take rates were achieved for 7 of the 8 cell lines (MCF-7, T47D, MDA.MB.231, PEO1, PEO1 cDDPr, PEO4 and PEO14); in the remaining cell line [OV(hyg)CAR3] 2/6 (33%) tumours grew. Xenografts established with Matrigel could be transferred into recipient animals and grown in the absence of Matrigel, suggesting that Matrigel is necessary only for initial establishment of tumours. Furthermore, cells which had been re-established from a T47D xenograft and then inoculated into mice without Matrigel showed a take rate greater than that of the original cell line but less than that of the xenograft. In conclusion, Matrigel has proven to be extremely useful in establishing a variety of cell lines as xenografts.
Emmanuelle Sarzi - One of the best experts on this subject based on the ideXlab platform.
-
twinkle helicase PEO1 gene mutation causes mitochondrial dna depletion
Annals of Neurology, 2007Co-Authors: Emmanuelle Sarzi, Steffi Goffart, Valérie Serre, Dominique Chretien, A. Slama, Arnold Munnich, Johannes N. Spelbrink, Agnès RötigAbstract:Objective Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically and genetically heterogeneous group of autosomal recessive diseases characterized by a reduction in mtDNA copy number. Several nuclear genes have been shown to account for these severe oxidative phosphorylation disorders, but the disease-causing mutations remain largely unknown. Methods By virtue of homozygosity mapping, we tested candidate genes involved in mtDNA maintenance in patients born to consanguineous parents. Results We found homozygosity for microsatellite markers flanking the PEO1 gene, encoding the mitochondrial Twinkle helicase, in two sibs presenting a hepatocerebral form of MDS. Sequencing the PEO1 gene showed a homozygous mutation at a conserved position of the protein in the two patients (T457I). The modeling of the Twinkle protein showed that T457 is located in the interface between two monomers of the hexameric enzyme. Finally, using purified recombinant protein, we demonstrated that the T457I mutant Twinkle has a defective helicase activity. Interpretation Although dominant Twinkle mutations have been previously reported in patients with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions, we report here the first recessive Twinkle mutation in patients with hepatocerebral form of MDS. Identifying other Twinkle mutations in MDS and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on the isolated proteins should help in understanding why some mutations are recessive and others are dominant. Ann Neurol 2007
-
Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.
Annals of neurology, 2007Co-Authors: Emmanuelle Sarzi, Steffi Goffart, Valérie Serre, Dominique Chretien, A. Slama, Arnold Munnich, Johannes N. Spelbrink, Agnès RötigAbstract:Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically and genetically heterogeneous group of autosomal recessive diseases characterized by a reduction in mtDNA copy number. Several nuclear genes have been shown to account for these severe oxidative phosphorylation disorders, but the disease-causing mutations remain largely unknown. By virtue of homozygosity mapping, we tested candidate genes involved in mtDNA maintenance in patients born to consanguineous parents. We found homozygosity for microsatellite markers flanking the PEO1 gene, encoding the mitochondrial Twinkle helicase, in two sibs presenting a hepatocerebral form of MDS. Sequencing the PEO1 gene showed a homozygous mutation at a conserved position of the protein in the two patients (T457I). The modeling of the Twinkle protein showed that T457 is located in the interface between two monomers of the hexameric enzyme. Finally, using purified recombinant protein, we demonstrated that the T457I mutant Twinkle has a defective helicase activity. Although dominant Twinkle mutations have been previously reported in patients with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions, we report here the first recessive Twinkle mutation in patients with hepatocerebral form of MDS. Identifying other Twinkle mutations in MDS and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on the isolated proteins should help in understanding why some mutations are recessive and others are dominant.
David J. Harrison - One of the best experts on this subject based on the ideXlab platform.
-
The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer.
Oncotarget, 2015Co-Authors: Rui Huang, Simon P. Langdon, Peter Mullen, Dana Faratian, Matthew Tse, David J. HarrisonAbstract:Chromatin undergoes structural changes in response to extracellular and environmental signals. We observed changes in nuclear morphology in cancer tissue biopsied after chemotherapy and hypothesised that these DNA damage-induced changes are mediated by histone deacetylases (HDACs). Nuclear morphological changes in cell lines (PE01 and PE04 models) and a xenograft model (OV1002) were measured in response to platinum chemotherapy by image analysis of nuclear texture. HDAC2 expression increased in PEO1 cells treated with cisplatin at 24h, which was accompanied by increased expression of heterochromatin protein 1 (HP1). HDAC2 and HP1 expression were also increased after carboplatin treatment in the OV1002 carboplatin-sensitive xenograft model but not in the insensitive HOX424 model. Expression of DNA damage response pathways (pBRCA1, γH2AX, pATM, pATR) showed time-dependent changes after cisplatin treatment. HDAC2 knockdown by siRNA reduced HP1 expression, induced DNA double strand breaks (DSB) measured by γH2AX, and interfered with the activation of DNA damage response induced by cisplatin. Furthermore, HDAC2 depletion affected γH2AX foci formation, cell cycle distribution, and apoptosis triggered by cisplatin, and was additive to the inhibitory effect of cisplatin in cell lines. By inhibiting expression of HDAC2, reversible alterations in chromatin patterns during cisplatin treatment were observed. These results demonstrate quantifiable alterations in nuclear morphology after chemotherapy, and implicate HDAC2 in higher order chromatin changes and cellular DNA damage responses in ovarian cancer cells in vitro and in vivo.
-
Abstract 4085: The roles of HDACs in chromatin remodelling and response to chemotherapy in cancer
Molecular and Cellular Biology, 2012Co-Authors: Rui Huang, Simon P. Langdon, David J. Harrison, Dana FaratianAbstract:Background: Chromatin is dynamic in higher-order structure in response to extracellular and environmental signals. We observed nuclear morphological changes in clinical cancer tissues after chemotherapy. Since chromatin structure dictates gene expression, and therefore function, further investigation of this phenomenon may help us to better understand therapeutic responses. We hypothesise that nuclear morphological changes in cancer in response to DNA-damage by chemotherapy are mediated by histone deacetylases (HDACs). Methods: Ovarian cancer cell lines PEO1/PEO4 (platinum sensitive/resistant) were selected as in vitro models, and primary ovarian cancer xenografts OV1002 and HOX424 as in vivo models. Expression levels of HDACs and heterochromatin protein 1 (HP1) were screened by reverse phase protein array (RPPA) and western blot after treatment with cisplatin. Immunofluorescence imaging was undertaken using confocal microscopy and nuclear texture was measured in Image J using GLCM texture analysis plugin. 38 ovarian cancer patient and 175 xenograft samples were assessed for HDAC and HP1 expression in response to chemotherapy by quantitative immunofluorescence. HDAC2 expression was modulated by interfering RNAs (siRNA). Results: We demonstrate nuclear morphological changes in clinical tumours, xenografts, and cell lines in response to platinum chemotherapy. HDACs and HP1 isoforms showed differential expression in a panel of 25 ovarian cancer cell lines associated with response to chemotherapy with increased expression in treated or resistant lines. Expression of HDACs increased in PEO1 cells treated with cisplatin in a time-dependent fashion. This was accompanied by quantifiable changes in nuclear texture (increased heterogeneity), and high expression of HP1s at early time point (4-24h). The proliferation of PEO1 cells was inhibited and HP1 protein expression decreased after HDAC2 knockdown. In clinical specimens, HDAC8 and HP1 gamma expression significantly increased after chemotherapy, and class I HDAC (1, 2, and 8) and HP1 expression were increased after carboplatin treatment in carboplatin-sensitive xenografts. Chromatin conformation, DNA damage response, and cell cycle progression showed sequential changes over time with carboplatin treatment. Conclusion: These results demonstrate alterations in chromatin structure after chemotherapy, and implicate the role of class I HDACs in higher order chromatin changes and the DNA damage response in ovarian cancer in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4085. doi:1538-7445.AM2012-4085
-
WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3
Cancer research, 2009Co-Authors: Charlie Gourley, Jieqing Zhang, David J. Harrison, Adam J.w. Paige, Karen J. Taylor, Carol Ward, Barbara Kuske, Mingjun Sun, Szymon Janczar, Morwenna MuirAbstract:The WW domain-containing oxidoreductase (WWOX) gene is located at FRA16D, a common fragile site involved in human cancer. Targeted deletion of Wwox in mice causes increased spontaneous tumor incidence, confirming that WWOX is a bona fide tumor suppressor gene. We show that stable transfection of WWOX into human PEO1 ovarian cancer cells, containing homozygous WWOX deletion, abolishes in vivo tumorigenicity, but this does not correlate with alteration of in vitro growth. Rather, WWOX restoration in PEO1, or WWOX overexpression in SKOV3 ovarian cancer cells, results in reduced attachment and migration on fibronectin, an extracellular matrix component linked to peritoneal metastasis. Conversely, siRNA-mediated knockdown of endogenous WWOX in A2780 ovarian cancer cells increases adhesion to fibronectin. In addition, whereas there is no WWOX-dependent difference in cell death in adherent cells, WWOX-transfected cells in suspension culture display a proapoptotic phenotype. We further show that WWOX expression reduces membranous integrin alpha(3) protein but not integrin alpha(3) mRNA levels, and that adhesion of PEO1 cells to fibronectin is predominantly mediated through integrin alpha(3). We therefore propose that WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix and by inducing apoptosis in detached cells. Consistent with this, the suppression of PEO1 tumorigenicity by WWOX can be partially overcome by implanting these tumor cells in Matrigel. These data suggest a possible role for the loss of WWOX in the peritoneal dissemination of human ovarian cancer cells.
Charlie Gourley - One of the best experts on this subject based on the ideXlab platform.
-
HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer
Cancer research, 2011Co-Authors: Euan A. Stronach, Albandri Alfraidi, Nona Rama, Christoph Datler, James B. Studd, Roshan Agarwal, Tankut G. Guney, Charlie Gourley, Bryan T. Hennessy, Gordon B. MillsAbstract:Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests resistant clones exist within a larger drug sensitive cell-population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically-derived, intra-patient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell-line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 down-regulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of HDAC4, FOLR2, PIK3R1 or STAT1 (p
-
WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3
Cancer research, 2009Co-Authors: Charlie Gourley, Jieqing Zhang, David J. Harrison, Adam J.w. Paige, Karen J. Taylor, Carol Ward, Barbara Kuske, Mingjun Sun, Szymon Janczar, Morwenna MuirAbstract:The WW domain-containing oxidoreductase (WWOX) gene is located at FRA16D, a common fragile site involved in human cancer. Targeted deletion of Wwox in mice causes increased spontaneous tumor incidence, confirming that WWOX is a bona fide tumor suppressor gene. We show that stable transfection of WWOX into human PEO1 ovarian cancer cells, containing homozygous WWOX deletion, abolishes in vivo tumorigenicity, but this does not correlate with alteration of in vitro growth. Rather, WWOX restoration in PEO1, or WWOX overexpression in SKOV3 ovarian cancer cells, results in reduced attachment and migration on fibronectin, an extracellular matrix component linked to peritoneal metastasis. Conversely, siRNA-mediated knockdown of endogenous WWOX in A2780 ovarian cancer cells increases adhesion to fibronectin. In addition, whereas there is no WWOX-dependent difference in cell death in adherent cells, WWOX-transfected cells in suspension culture display a proapoptotic phenotype. We further show that WWOX expression reduces membranous integrin alpha(3) protein but not integrin alpha(3) mRNA levels, and that adhesion of PEO1 cells to fibronectin is predominantly mediated through integrin alpha(3). We therefore propose that WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix and by inducing apoptosis in detached cells. Consistent with this, the suppression of PEO1 tumorigenicity by WWOX can be partially overcome by implanting these tumor cells in Matrigel. These data suggest a possible role for the loss of WWOX in the peritoneal dissemination of human ovarian cancer cells.