Advanced search
1 file | 2.78 MB Add to list

ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition

Nicolas Skrypek (UGent) , Kenneth Bruneel (UGent) , Cindy Vandewalle (UGent) , Eva De Smedt (UGent) , Bieke Soen (UGent) , Nele Loret (UGent) , Joachim Taminau (UGent) , Steven Goossens (UGent) , Niels Vandamme (UGent) and Geert Berx (UGent)
Author
Organization
Abstract
Background: Epithelial mesenchymal transition (EMT) is tightly regulated by a network of transcription factors (EMT-TFs). Among them is the nuclear factor ZEB2, a member of the zinc-finger E-box binding homeobox family. ZEB2 nuclear localization has been identified in several cancer types, and its overexpression is correlated with the malignant progression. ZEB2 transcriptionally represses epithelial genes, such as E-cadherin (CDH1), by directly binding to the promoter of the genes it regulates and activating mesenchymal genes by a mechanism in which there is no full agreement. Recent studies showed that EMT-TFs interact with epigenetic regulatory enzymes that alter the epigenome, thereby providing another level of control. The role of epigenetic regulation on ZEB2 function is not well understood. In this study, we aimed to characterize the epigenetic effect of ZEB2 repressive function on the regulation of a small Rab GTPase RAB25. Results: Using cellular models with conditional ZEB2 expression, we show a clear transcriptional repression of RAB25 and CDH1. RAB25 contributes to the partial suppression of ZEB2-mediated cell migration. Furthermore, a highly significant reverse correlation between RAB25 and ZEB2 expression in several human cancer types could be identified. Mechanistically, ZEB2 binds specifically to E-box sequences on the RAB25 promoter. ZEB2 binding is associated with the local increase in DNA methylation requiring DNA methyltransferases as well as histone deacetylation (H3K9Ac) depending on the activity of SIRT1. Surprisingly, SIRT1 and DNMTs did not interact directly with ZEB2, and while SIRT1 inhibition decreased the stability of long-term repression, it did not prevent down-regulation of RAB25 and CDH1 by ZEB2. Conclusions: ZEB2 expression is resulting in drastic changes at the chromatin level with both clear DNA hypermethylation and histone modifications. Here, we revealed that SIRT1-mediated H3K9 deacetylation helps to maintain gene repression but is not required for the direct ZEB2 repressive function. Targeting epigenetic enzymes to prevent EMT is an appealing approach to limit cancer dissemination, but inhibiting SIRT1 activity alone might have limited effect and will require drug combination to efficiently prevent EMT.
Keywords
EMT, ZEB2, Epigenetic regulation, RAB25, SIRT1, DNMT, PANCREATIC-CANCER CELLS, E-CADHERIN PROMOTER, DNA METHYLATION, BREAST-CANCER, TRANSCRIPTION FACTORS, LUNG-CANCER, STEM-CELLS, METASTASIS, CARCINOMA, EMT

Downloads

  • 4052 18Skrypek.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 2.78 MB

Citation

Please use this url to cite or link to this publication:

MLA
Skrypek, Nicolas et al. “ZEB2 Stably Represses RAB25 Expression Through Epigenetic Regulation by SIRT1 and DNMTs During Epithelial-to-mesenchymal Transition.” EPIGENETICS & CHROMATIN 11 (2018): n. pag. Print.
APA
Skrypek, N., Bruneel, K., Vandewalle, C., De Smedt, E., Soen, B., Loret, N., Taminau, J., et al. (2018). ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition. EPIGENETICS & CHROMATIN, 11.
Chicago author-date
Skrypek, Nicolas, Kenneth Bruneel, Cindy Vandewalle, Eva De Smedt, Bieke Soen, Nele Loret, Joachim Taminau, Steven Goossens, Niels Vandamme, and Geert Berx. 2018. “ZEB2 Stably Represses RAB25 Expression Through Epigenetic Regulation by SIRT1 and DNMTs During Epithelial-to-mesenchymal Transition.” Epigenetics & Chromatin 11.
Chicago author-date (all authors)
Skrypek, Nicolas, Kenneth Bruneel, Cindy Vandewalle, Eva De Smedt, Bieke Soen, Nele Loret, Joachim Taminau, Steven Goossens, Niels Vandamme, and Geert Berx. 2018. “ZEB2 Stably Represses RAB25 Expression Through Epigenetic Regulation by SIRT1 and DNMTs During Epithelial-to-mesenchymal Transition.” Epigenetics & Chromatin 11.
Vancouver
1.
Skrypek N, Bruneel K, Vandewalle C, De Smedt E, Soen B, Loret N, et al. ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition. EPIGENETICS & CHROMATIN. 2018;11.
IEEE
[1]
N. Skrypek et al., “ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition,” EPIGENETICS & CHROMATIN, vol. 11, 2018.
@article{8582748,
  abstract     = {Background: Epithelial mesenchymal transition (EMT) is tightly regulated by a network of transcription factors (EMT-TFs). Among them is the nuclear factor ZEB2, a member of the zinc-finger E-box binding homeobox family. ZEB2 nuclear localization has been identified in several cancer types, and its overexpression is correlated with the malignant progression. ZEB2 transcriptionally represses epithelial genes, such as E-cadherin (CDH1), by directly binding to the promoter of the genes it regulates and activating mesenchymal genes by a mechanism in which there is no full agreement. Recent studies showed that EMT-TFs interact with epigenetic regulatory enzymes that alter the epigenome, thereby providing another level of control. The role of epigenetic regulation on ZEB2 function is not well understood. In this study, we aimed to characterize the epigenetic effect of ZEB2 repressive function on the regulation of a small Rab GTPase RAB25. 
Results: Using cellular models with conditional ZEB2 expression, we show a clear transcriptional repression of RAB25 and CDH1. RAB25 contributes to the partial suppression of ZEB2-mediated cell migration. Furthermore, a highly significant reverse correlation between RAB25 and ZEB2 expression in several human cancer types could be identified. Mechanistically, ZEB2 binds specifically to E-box sequences on the RAB25 promoter. ZEB2 binding is associated with the local increase in DNA methylation requiring DNA methyltransferases as well as histone deacetylation (H3K9Ac) depending on the activity of SIRT1. Surprisingly, SIRT1 and DNMTs did not interact directly with ZEB2, and while SIRT1 inhibition decreased the stability of long-term repression, it did not prevent down-regulation of RAB25 and CDH1 by ZEB2. 
Conclusions: ZEB2 expression is resulting in drastic changes at the chromatin level with both clear DNA hypermethylation and histone modifications. Here, we revealed that SIRT1-mediated H3K9 deacetylation helps to maintain gene repression but is not required for the direct ZEB2 repressive function. Targeting epigenetic enzymes to prevent EMT is an appealing approach to limit cancer dissemination, but inhibiting SIRT1 activity alone might have limited effect and will require drug combination to efficiently prevent EMT.},
  articleno    = {70},
  author       = {Skrypek, Nicolas and Bruneel, Kenneth and Vandewalle, Cindy and De Smedt, Eva and Soen, Bieke and Loret, Nele and Taminau, Joachim and Goossens, Steven and Vandamme, Niels and Berx, Geert},
  issn         = {1756-8935},
  journal      = {EPIGENETICS & CHROMATIN},
  keywords     = {EMT,ZEB2,Epigenetic regulation,RAB25,SIRT1,DNMT,PANCREATIC-CANCER CELLS,E-CADHERIN PROMOTER,DNA METHYLATION,BREAST-CANCER,TRANSCRIPTION FACTORS,LUNG-CANCER,STEM-CELLS,METASTASIS,CARCINOMA,EMT},
  language     = {eng},
  pages        = {15},
  title        = {ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition},
  url          = {http://dx.doi.org/10.1186/s13072-018-0239-4},
  volume       = {11},
  year         = {2018},
}

Altmetric
View in Altmetric
Web of Science
Times cited: