Researcher:
Kahya, Zeynep

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Zeynep

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Kahya

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Kahya, Zeynep
Kahya Yeşil, Zeynep

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2017 - 20192

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Researcher Of Publications: search.filters.isAuthorOfPublication.b4a50616-fcf0-4b0e-b506-763a1ddfb182

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    PublicationOpen Access
    Kdm2b, an h3k36-specific demethylase, regulates apoptotic response of gbm cells to trail
    (Nature Publishing Group (NPG), 2017) Gumus, Zeynep H.; Kurt, İbrahim Çağrı; Sur, İlknur Erdem; Kaya, Ezgi; Cingöz, Ahmet; Kazancıoğlu, Selena; Kahya, Zeynep; Toparlak, Ömer Duhan; Şenbabaoğlu, Filiz; Kaya, Zeynep; Özyerli, Ezgi; Karahüseyinoğlu, Serçin; Lack, Nathan Alan; Önder, Tamer Tevfik; Önder, Tuğba Bağcı; PhD Student; Undergraduate Student; Other; PhD Student; Faculty Member; Faculty Member; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 110772; 120842; 42946; 184359
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells. TRAIL resistance in cancers is associated with aberrant expression of the key components of the apoptotic program. However, how these components are regulated at the epigenetic level is not understood. In this study, we investigated novel epigenetic mechanisms regulating TRAIL response in glioblastoma multiforme (GBM) cells by a short-hairpin RNA loss-of-function screen. We interrogated 48 genes in DNA and histone modification pathways and identified KDM2B, an H3K36-specific demethylase, as a novel regulator of TRAIL response. Accordingly, silencing of KDM2B significantly enhanced TRAIL sensitivity, the activation of caspase-8, -3 and -7 and PARP cleavage. KDM2B knockdown also accelerated the apoptosis, as revealed by live-cell imaging experiments. To decipher the downstream molecular pathways regulated by KDM2B, levels of apoptosis-related genes were examined by RNA-sequencing upon KDM2B loss, which revealed derepression of proapoptotic genes Harakiri (HRK), caspase-7 and death receptor 4 (DR4) and repression of antiapoptotic genes. The apoptosis phenotype was partly dependent on HRK upregulation, as HRK knockdown significantly abrogated the sensitization. KDM2B-silenced tumors exhibited slower growth in vivo. Taken together, our findings suggest a novel mechanism, where the key apoptosis components are under epigenetic control of KDM2B in GBM cells.
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    PublicationOpen Access
    The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma
    (Nature Publishing Group (NPG), 2019) Gezen, Melike; Tolay, Nazife; Erman, Batu; Dunford, James; Oppermann, Udo; N/A; Department of Industrial Engineering; Department of Molecular Biology and Genetics; N/A; Uyulur, Fırat; Gönen, Mehmet; Önder, Tuğba Bağcı; Özyerli, Ezgi; Sur, İlknur Erdem; Şeker-Polat, Fidan; Cingöz, Ahmet; Kayabölen, Alişan; Kahya, Zeynep; Faculty Member; Department of Industrial Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; Graduate School of Health Sciences; N/A; 237468; 184359; N/A; N/A; N/A; N/A; N/A; N/A
    Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells. GBM cells frequently develop resistance to TRAIL which renders clinical application of TRAIL therapeutics inefficient. In this study, we undertook a chemical screening approach using a library of epigenetic modifier drugs to identify compounds that could augment TRAIL response. We identified the fungal metabolite chaetocin, an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through ROS generation and consequent DNA damage induction that involved P53 activity. Chaetocin induced transcriptomic changes showed induction of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent and HMOX1 depletion enhanced chaetocin mediated TRAIL sensitization. Finally, chaetocin and TRAIL combination treatment revealed efficacy in vivo. Taken together, our results provide a novel role for chaetocin as an apoptosis priming agent and its combination with pro-apoptotic therapies might offer new therapeutic approaches for GBMs.