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Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer

ABSTRACT: This paper shows, for the first time, a novel function of the OVO-like proteins (OVOL1and OVOL2) as critical inducers of mesenchymal to epithelial transition (MET) in human cancer. Examination of the effects of OVOL1 and OVOL2 overexpression in a prostate cancer model.

ORGANISM(S): Homo sapiens

SUBMITTER: Richard McEachin

PROVIDER: E-GEOD-48230 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer.

Roca Hernan H Hernandez James J Weidner Savannah S McEachin Richard C RC Fuller David D Sud Sudha S Schumann Taibriana T Wilkinson John E JE Zaslavsky Alexander A Li Hangwen H Maher Christopher A CA Daignault-Newton Stephanie S Healy Patrick N PN Pienta Kenneth J KJ

PloS one 20131004 10

Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and t ...[more]

PMID: 24124593

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A bioinformatics approach reveals novel mechanisms of the OVOL transcription factors in the regulation of epithelial-mesenchymal cell programming and cancer progression.

Project description:We find significant evidence of the OVOL, AP1, STAT1, STAT3, and NFKB1 TFs having important roles in MET. We prioritize known gene/drug targets for follow-up in the clinic, and show that the AP1/MYC TF pair is a strong candidate for intervention. Examination of the effects of OVOL1 and OVOL2 overexpression common to prostate cancer and breast cancer models.

2014-03-20 | E-GEOD-51975 | biostudies-arrayexpress

Expression data from isolated E16.5 mouse skin with or without Ovol2 overexpression

Project description:During epithelial tissue morphogenesis, developmental progenitor cells undergo dynamic adhesive and cytoskeletal remodeling to trigger proliferation and migration. Transcriptional mechanisms that restrict such mild form of epithelial plasticity to maintain lineage-restricted differentiation in committed epithelial tissues are poorly understood. Here we report that simultaneous ablation of transcriptional repressor-encoding Ovol1 and Ovol2 results in expansion and blocked terminal differentiation of embryonic epidermal progenitor cells. Conversely, mice overexpressing Ovol2 in their skin epithelia exhibit precocious differentiation accompanied by smaller progenitor cell compartments. We show that Ovol1/2-deficient epidermal cells fail to undertake alpha-catenin–driven actin cytoskeletal reorganization and adhesive maturation, and exhibit changes that resemble epithelial-to-mesenchymal transition (EMT). Remarkably, these alterations as well as defective terminal differentiation are reversed upon depletion of EMT-promoting transcriptional factor Zeb1. Collectively, our findings reveal Ovol-Zeb1-a-catenin sequential repression and highlight novel functions of Ovol as gatekeepers of epithelial adhesion and differentiation by inhibiting progenitor-like traits and epithelial plasticity. Skin from control and Ovol2 overexpression (Ovol2 BT) were physically isolated for RNA extraction and hybridization on Affymetrix microarrays. In order to identify primary changes, we analyzed skin from E16.5 mice, when morphological differences between control and Ovol2 overexpression were still minimal.

2015-02-14 | E-GEOD-55073 | biostudies-arrayexpress

Expression data from isolated E17.5 mouse skin with or without Ovol2 overexpression

Project description:During epithelial tissue morphogenesis, developmental progenitor cells undergo dynamic adhesive and cytoskeletal remodeling to trigger proliferation and migration. Transcriptional mechanisms that restrict such mild form of epithelial plasticity to maintain lineage-restricted differentiation in committed epithelial tissues are poorly understood. Here we report that simultaneous ablation of transcriptional repressor-encoding Ovol1 and Ovol2 results in expansion and blocked terminal differentiation of embryonic epidermal progenitor cells. Conversely, mice overexpressing Ovol2 in their skin epithelia exhibit precocious differentiation accompanied by smaller progenitor cell compartments. We show that Ovol1/2-deficient epidermal cells fail to undertake alpha-catenin–driven actin cytoskeletal reorganization and adhesive maturation, and exhibit changes that resemble epithelial-to-mesenchymal transition (EMT). Remarkably, these alterations as well as defective terminal differentiation are reversed upon depletion of EMT-promoting transcriptional factor Zeb1. Collectively, our findings reveal Ovol-Zeb1-a-catenin sequential repression and highlight novel functions of Ovol as gatekeepers of epithelial adhesion and differentiation by inhibiting progenitor-like traits and epithelial plasticity. Skin from control and Ovol2 overexpression (Ovol2 BT) were physically isolated for RNA extraction and hybridization on Affymetrix microarrays. In order to identify changes in differentiation of the epidermis, we analyzed skin from E17.5 mice, when differentiation of the epidermis was more advanced.

2015-02-14 | E-GEOD-55074 | biostudies-arrayexpress

Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer

Project description:This paper shows, for the first time, a novel function of the OVO-like proteins (OVOL1and OVOL2) as critical inducers of mesenchymal to epithelial transition (MET) in human cancer.

2013-08-01 | GSE48230 | GEO

Effect of OVO-like 1 knockdown on global transcript expression in differentiated BeWo trophoblast cells

Project description:We had previously discovered that the transcription factor OVO-like 1 (OVOL1) was highly induced during trophoblast differentiation. In this study, we used an lentiviral shRNA strategy to decrease OVOL1 expression in BeWo trophoblast cells. Control cells were transduced with shRNAs targeting no known mammalian transcript (shCont). Following stimulation of differentiation (48h exposure to 8-bromo-cyclic adenosine monophosphate), a RNA-seq approach was used to determine global transcript differences in OVOL1-knockdown cells compared to control cells. Trophoblast cells transduced with control shRNAs were used as controls. Cells transduced with shRNAs targeting OVOL1 were used as treatment. All cells received 250 uM 8-bromo-cyclic adenosine monophosphate to stimulate differentiation. Three independent replicates of control and treatment groups were analyzed.

2015-08-01 | E-GEOD-66962 | biostudies-arrayexpress

Expression data from isolated keratinocytes from mouse skin with or without Ovol1 and Ovol2 expression

Project description:During epithelial tissue morphogenesis, developmental progenitor cells undergo dynamic adhesive and cytoskeletal remodeling to trigger proliferation and migration. Transcriptional mechanisms that restrict such mild form of epithelial plasticity to maintain lineage-restricted differentiation in committed epithelial tissues are poorly understood. Here we report that simultaneous ablation of transcriptional repressor-encoding Ovol1 and Ovol2 results in expansion and blocked terminal differentiation of embryonic epidermal progenitor cells. Conversely, mice overexpressing Ovol2 in their skin epithelia exhibit precocious differentiation accompanied by smaller progenitor cell compartments. We show that Ovol1/2-deficient epidermal cells fail to undertake alpha-catenin–driven actin cytoskeletal reorganization and adhesive maturation, and exhibit changes that resemble epithelial-to-mesenchymal transition (EMT). Remarkably, these alterations as well as defective terminal differentiation are reversed upon depletion of EMT-promoting transcriptional factor Zeb1. Collectively, our findings reveal Ovol-Zeb1-a-catenin sequential repression and highlight novel functions of Ovol as gatekeepers of epithelial adhesion and differentiation by inhibiting progenitor-like traits and epithelial plasticity. Isolated keratinocytes from control, Ovol1 knockout and Ovol1/2 double knockout were physically isolated for RNA extraction and hybridization on Affymetrix microarrays. In order to identify primary changes, we isolated the keratinocytes from mouse skin and allowed them to grow in culture for 2-5 days.

2015-02-14 | E-GEOD-55072 | biostudies-arrayexpress

Transcriptome analysis of MCF10A-M2 cells upon the depletion of OVOL1 or OVOL2

Project description:OVOL1 protein was shown to be downregulated in breast cancer patient samples and was inversely correlated with the epithelial-to-mesenchymal transition (EMT) signature. To better dissect the downstream target genes and elucidate the signaling pathways altered by OVOL1, we deplete OVOL1 by the specific siRNA in MCF10A-M2 cells. To set as a control, OVOL2 was knockdown by the specific siRNA in the same cell line. The total RNA was collected and sent for RNA sequencing analysis. Afterwards, the differentially expressd genes were used for the pathway enrichment analysi and the gene set enrichment analysis (GSEA).

2021-12-26 | GSE192548 | GEO

Expression data from calcium-induced isolated keratinocytes from mouse skin with or without Ovol1 and Ovol2 expression

Project description:During epithelial tissue morphogenesis, developmental progenitor cells undergo dynamic adhesive and cytoskeletal remodeling to trigger proliferation and migration. Transcriptional mechanisms that restrict such mild form of epithelial plasticity to maintain lineage-restricted differentiation in committed epithelial tissues are poorly understood. Here we report that simultaneous ablation of transcriptional repressor-encoding Ovol1 and Ovol2 results in expansion and blocked terminal differentiation of embryonic epidermal progenitor cells. Conversely, mice overexpressing Ovol2 in their skin epithelia exhibit precocious differentiation accompanied by smaller progenitor cell compartments. We show that Ovol1/2-deficient epidermal cells fail to undertake alpha-catenin–driven actin cytoskeletal reorganization and adhesive maturation, and exhibit changes that resemble epithelial-to-mesenchymal transition (EMT). Remarkably, these alterations as well as defective terminal differentiation are reversed upon depletion of EMT-promoting transcriptional factor Zeb1. Collectively, our findings reveal Ovol-Zeb1-a-catenin sequential repression and highlight novel functions of Ovol as gatekeepers of epithelial adhesion and differentiation by inhibiting progenitor-like traits and epithelial plasticity. Isolated keratinocytes from control, Ovol1 knockout and Ovol1/2 double knockout were physically isolated for RNA extraction and hybridization on Affymetrix microarrays. In order to identify differentiation changes, we isolated the keratinocytes from mouse skin and allowed them to grow in culture for 2-5 days, then added calcium and allowed them to grow another 3-5 days.

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Expression data from isolated E17.5 mouse skin with or without Ovol2 overexpression

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Expression data from isolated E16.5 mouse skin with or without Ovol2 overexpression

2015-02-14 | GSE55073 | GEO