| dc.contributor.advisor | Johnsen, Steven Prof. Dr. | |
| dc.contributor.author | Mishra, Vivek Kumar | |
| dc.date.accessioned | 2017-04-03T08:18:34Z | |
| dc.date.available | 2017-04-03T08:18:34Z | |
| dc.date.issued | 2017-04-03 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0023-3DFE-E | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-6231 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Epigenetic Regulation of Tumor Cell Phenotype | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Johnsen, Steven Prof. Dr. | |
| dc.date.examination | 2016-06-08 | |
| dc.description.abstracteng | The Transforming Growth Factor-β (TGFβ)/SMAD signaling pathway can function as
either a tumor suppressor or metastasis promoter during tumor progression. In normal
epithelial cells and early stages of epithelial tumorigenesis TGFβ functions as a tumor
suppressor to decrease cell proliferation or induce apoptosis. However, during
malignant progression tumor cells no longer respond to the anti-proliferative effects of
TGFβ, but instead undergo an epithelial-to-mesenchymal transition (EMT) whereby
cells acquire a migratory and invasive phenotype which promotes tumor metastasis.
Resolution of the dichotomy in TGFβ function and a further understanding of its tumor
suppressor and metastasis promoting functions may uncover new strategies for the
treatment of epithelial cancers. Previous studies have demonstrated an important role
of the TGFβ-Inducible Early Gene-1 (TIEG1)/Krüppel-like Factor-10 (KLF10) as a
central regulator of TGFβ/SMAD signaling and the anti-proliferative functions of TGFβ.
In this study we examined the role of KLF10 in controlling the TGFβ-induced EMT and
show that depletion of KLF10 results in a more pronounced induction of EMT.
Moreover, chromatin immunoprecipitation (ChIP) and chromatin immunoprecipitation-
sequencing (ChIP-seq) analysis shows that KLF10 directly binds to GC-rich
sequences in the promoter region of the EMT-promoting transcription factor
SLUG/SNAI2 to repress its transcription. Consistent with these findings, an analysis
of KLF10 in lung cancer revealed that KLF10 levels are decreased in lung cancer vs.
normal samples. Furthermore, in vivo study revealed a significantly increased tumor
incidence and tumor size in Klf10-/- mice compared to the wild type mice. Additional
ChIP studies showed that KLF10 recruits HDAC1 to the SNAI2 promoter and is
required for the removal of activating histone acetylation marks. These findings reveal
a previously unknown function of KLF10 in suppressing TGFβ-induced EMT and
Abstract
x
represent a significant advancement in the understanding the molecular dichotomy of
TGFβ function during tumor progression.
In a more global approach, we have utilized a dual LSD1/HDAC inhibitor 4SC-202 to
study the effect on tumor cell phenotype. We have shown that combined inhibition of
LSD1 and HDACs significantly block the TGFβ-induced EMT. Immunohistochemical
staining of LSD1 in pancreatic cancer samples revealed that LSD1 is highly expressed
in a subset of tumors. Consistent with this finding, in our xenograft study we have
shown that 4SC-202 significantly decreases the tumor size. Together these findings
revealed the potential role of small molecule inhibitors against epigenetic modifiers in
targeted anticancer therapy. | de |
| dc.contributor.coReferee | Dobbelstein, Matthias Prof. Dr. | |
| dc.subject.eng | Cancer, Epigenetics, EMT, Metastasis, HDAC | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0023-3DFE-E-0 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 883808129 | |