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Epigenetic Regulation of Tumor Cell Phenotype

dc.contributor.advisorJohnsen, Steven Prof. Dr.
dc.contributor.authorMishra, Vivek Kumar
dc.titleEpigenetic Regulation of Tumor Cell Phenotypede
dc.contributor.refereeJohnsen, Steven Prof. Dr.
dc.description.abstractengThe 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
dc.contributor.coRefereeDobbelstein, Matthias Prof. Dr.
dc.subject.engCancer, Epigenetics, EMT, Metastasis, HDACde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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