Researcher:
Morova, Tunç

Profile Picture
ORCID

Job Title

Master Student

First Name

Tunç

Last Name

Morova

Name

Name Variants

Morova, Tunç

Email Address

Birth Date

Filters

2018 - 201932020 - 20223

Advanced Search

Filter by

Settings

Researcher Of Publications: search.filters.isAuthorOfPublication.beda7602-5d96-46b6-92af-52c94e77e616

Search Results

Now showing 1 - 6 of 6
  • Placeholder
    PublicationMetadata only
    Androgen receptor binding sites are highly mutated in prostate cancer
    (American Association for Cancer Research (AACR), 2018) N/A; Department of Industrial Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; N/A; Morova, Tunç; Gönen, Mehmet; Gürsoy, Attila; Keskin, Özlem; Lack, Nathan Alan; N/A; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Industrial Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; College of Engineering; College of Engineering; College of Engineering; School of Medicine; N/A; 237468; 8745; 26605; 120842
  • 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.
  • Placeholder
    PublicationMetadata only
    Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming
    (Nature Publishing Group (NPG), 2019) Cribbs, Adam P.; Philpott, Martin; Dunford, James E.; Ari, Sule; Oppermann, Udo; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Önder, Tamer Tevfik; Ebrahimi, Ayyub A.; Sevinç, Kenan; Sevinç, Gülben Gürhan; Uyulur, Fırat; Morova, Tunç; Göklemez, Sencer; Faculty Member; Researcher; PhD Student; PhD Student; Undergraduate Student; Master Student; Undergraduate Student; Department of Molecular Biology and Genetics; School of Medicine; School of Medicine; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; College of Sciences; Graduate School of Sciences and Engineering; School of Medicine; 42946; 381072; N/A; N/A; N/A; N/A; N/A
    Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.
  • Thumbnail Image
    PublicationOpen Access
    EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities
    (Nature Portfolio, 2022) Philpott, Martin; Cribbs, Adam P.; Kung, Sonia H.Y; Bayram, Özlem Yedier; Gökbayrak, Bengül; Kayabölen, Alişan; Aksu, Ali Cenk; Cavga, Ayşe Derya; Cingöz, Ahmet; Kala, Ezgi Yağmur; Karabıyık, Göktuğ; Esin, Beril; Morova, Tunç; Uyulur, Fırat; Önder, Tuğba Bağcı; Syed, Hamzah; Lack, Nathan Alan; Önder, Tamer Tevfik; PhD Student; Faculty Member; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 184359; 318138; 120842; 42946
    Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To interrogate the roles of epigenetic modifiers in cancer cells, we generated an epigenome-wide CRISPR-Cas9 knockout library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution and depletion of essential genes. We discovered novel epigenetic modifiers that regulate triple-negative breast cancer (TNBC) and prostate cancer cell fitness. We confirmed the growth-regulatory functions of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in TNBC cells. Overall, we show that EPIKOL, a focused sgRNA library targeting similar to 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness under in vitro and in vivo conditions and enable the identification of novel anti-cancer targets. Due to its comprehensive epigenome-wide targets and relatively high number of sgRNAs per gene, EPIKOL will facilitate studies examining functional roles of epigenetic modifiers in a wide range of contexts, such as screens in primary cells, patient-derived xenografts as well as in vivo models.
  • Thumbnail Image
    PublicationOpen Access
    Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer
    (Nature Publishing Group (NPG), 2019) Pires, Elisabete; McCullagh, James; Kawamura, Akane; Department of Molecular Biology and Genetics; N/A; N/A; Department of Molecular Biology and Genetics; N/A; Saraç, Hilal; Morova, Tunç; Kaplan, Anıl; Cingöz, Ahmet; Önder, Tuğba Bağcı; Önder, Tamer Tevfik; Lack, Nathan Alan; PhD Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; 184359; 42946; 120842
    Androgen deprivation therapy (ADT) is the standard care for prostate cancer (PCa) patients who fail surgery or radiotherapy. While initially effective, the cancer almost always recurs as a more aggressive castration resistant prostate cancer (CRPC). Previous studies have demonstrated that chromatin modifying enzymes can play a critical role in the conversion to CRPC. However, only a handful of these potential pharmacological targets have been tested. Therefore, in this study, we conducted a focused shRNA screen of chromatin modifying enzymes previously shown to be involved in cellular differentiation. We found that altering the balance between histone methylation and demethylation impacted growth and proliferation. Of all genes tested, KDM3B, a histone H3K9 demethylase, was found to have the most antiproliferative effect. These results were phenocopied with a KDM3B CRISPR/Cas9 knockout. When tested in several PCa cell lines, the decrease in proliferation was remarkably specific to androgen-independent cells. Genetic rescue experiments showed that only the enzymatically active KDM3B could recover the phenotype. Surprisingly, despite the decreased proliferation of androgen-independent cell no alterations in the cell cycle distribution were observed following KDM3B knockdown. Whole transcriptome analyses revealed changes in the gene expression profile following loss of KDM3B, including downregulation of metabolic enzymes such as ARG2 and RDH11. Metabolomic analysis of KDM3B knockout showed a decrease in several critical amino acids. Overall, our work reveals, for the first time, the specificity and the dependence of KDM3B in CRPC proliferation.
  • Thumbnail Image
    PublicationOpen Access
    Androgen receptor-binding sites are highly mutated in prostate cancer
    (Nature Publishing Group (NPG), 2020) McNeill, Daniel R.; Wilson, David M., III; Lallous, Nada; Dalal, Kush; Department of Industrial Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Morova, Tunç; Lack, Nathan Alan; Gönen, Mehmet; Gürsoy, Attila; Keskin, Özlem; Faculty Member; Faculty Member; Department of Industrial Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; College of Engineering; N/A; N/A; 237468; 8745; 26605
    Androgen receptor (AR) signalling is essential in nearly all prostate cancers. Any alterations to AR-mediated transcription can have a profound effect on carcinogenesis and tumor growth. While mutations of the AR protein have been extensively studied, little is known about those somatic mutations that occur at the non-coding regions where AR binds DNA. Using clinical whole genome sequencing, we show that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor and specific to only prostate cancer. Demonstrating this may be common to lineage-specific transcription factors, estrogen receptor binding sites were also found to have elevated rate of mutations in breast cancer. We provide evidence that these mutations at AR binding sites, and likely other related transcription factors, are caused by faulty repair of abasic sites. Overall, this work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and can impact enhancer activity.