Researcher:
Özyerli, Ezgi

Profile Picture
ORCID

Job Title

PhD Student

First Name

Ezgi

Last Name

Özyerli

Name

Name Variants

Özyerli, Ezgi
Özyerli Göknar, Ezgi

Email Address

Birth Date

Filters

2017 - 201922020 - 20212

Advanced Search

Filter by

Settings

Researcher Of Publications: search.filters.isAuthorOfPublication.ba99982f-cf07-46aa-bec8-bd9ef8489808

Search Results

Now showing 1 - 4 of 4
  • Placeholder
    PublicationMetadata only
    Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization
    (Springernature, 2021) Esai Selvan, Myvizhi; Bhere, Deepak; Shah, Khalid; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Cingöz, Ahmet; Özyerli, Ezgi; Morova, Tunç; Şeker-Polat, Fidan; Gümüş, Zeynep Hülya; Solaroğlu, İhsan; Önder, Tuğba Bağcı; Researcher; PhD Student; Master Student; PhD Student; Other; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; N/A; 102059; 184359
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor cell-specific apoptosis, making it a prime therapeutic candidate. However, many tumor cells are either innately TRAIL-resistant, or they acquire resistance with adaptive mechanisms that remain poorly understood. In this study, we generated acquired TRAIL resistance models using multiple glioblastoma (GBM) cell lines to assess the molecular alterations in the TRAIL-resistant state. We selected TRAIL-resistant cells through chronic and long-term TRAIL exposure and noted that they showed persistent resistance both in vitro and in vivo. Among known TRAIL-sensitizers, proteosome inhibitor Bortezomib, but not HDAC inhibitor MS-275, was effective in overcoming resistance in all cell models. This was partly achieved through upregulating death receptors and pro-apoptotic proteins, and downregulating major anti-apoptotic members, Bcl-2 and Bcl-xL. We showed that CRISPR/Cas9 mediated silencing of DR5 could block Bortezomib-mediated re-sensitization, demonstrating its critical role. While overexpression of Bcl-2 or Bcl-xL was sufficient to confer resistance to TRAIL-sensitive cells, it failed to override Bortezomib-mediated re-sensitization. With RNA sequencing in multiple paired TRAIL-sensitive and TRAIL-resistant cells, we identified major alterations in inflammatory signaling, particularly in the NF-kappa B pathway. Inhibiting NF-kappa B substantially sensitized the most resistant cells to TRAIL, however, the sensitization effect was not as great as what was observed with Bortezomib. Together, our findings provide new models of acquired TRAIL resistance, which will provide essential tools to gain further insight into the heterogeneous therapy responses within GBM tumors. Additionally, these findings emphasize the critical importance of combining proteasome inhibitors and pro-apoptotic ligands to overcome acquired resistance.
  • Thumbnail Image
    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.
  • Thumbnail Image
    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.
  • Thumbnail Image
    PublicationOpen Access
    Epigenetic deregulation of apoptosis in cancers
    (Multidisciplinary Digital Publishing Institute (MDPI), 2021) Önder, Tuğba Bağcı; Özyerli, Ezgi; Doctor; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 184359; N/A
    Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death.