Researcher:
Arabacı, Hilal Dilşad

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PhD Student

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Hilal Dilşad

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Arabacı

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Arabacı, Hilal Dilşad

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2021 - 20223

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    Going up the hill: chromatin-based barriers to epigenetic reprogramming
    (Wiley, 2021) Terzioglu, Gizem; Bayirbasi, Busra; N/A; N/A; Arabacı, Hilal Dilşad; Önder, Tamer Tevfik; PhD Student; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; N/A; 42946
    The establishment and maintenance of cellular identity are crucial during development and tissue homeostasis. Epigenetic mechanisms based largely on DNA methylation and histone modifications serve to reinforce and safeguard differentiated cell states. Somatic cell nuclear transfer (SCNT) or transcription factors such as Oct4, Sox2, Klf4, c-MYC (OSKM) can erase somatic cell identity and reprogram the cells to a pluripotent state. In doing so, reprogramming must reset the chromatin landscape, silence somatic-specific gene expression programs, and, in their place, activate the pluripotency network. In this viewpoint, we consider the major chromatin-based barriers for reprogramming of somatic cells to pluripotency. Among these, repressive chromatin modifications such as DNA methylation, H3K9 methylation, variant histone deposition, and histone deacetylation generally block the activation of pluripotency genes. In contrast, active transcription-associated chromatin marks such as DOT1L-catalyzed H3K79 methylation, FACT-mediated histone turnover, active enhancer SUMOylation, and EP300/CBP bromodomain-mediated interactions act to maintain somatic-specific gene expression programs. We highlight how genetic or chemical inhibition of both types of barriers can enhance the kinetics and/or efficiency of reprogramming. Understanding the mechanisms by which these barriers function provides insight into how chromatin marks help maintain cell identity.
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    PublicationOpen Access
    Metabolic reprogramming in adipose tissue during cancer cachexia
    (Frontiers, 2022) Department of Molecular Biology and Genetics; Weber, Bahar Zehra Camurdanoğlu; Arabacı, Hilal Dilşad; Kır, Serkan; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 274185
    Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.
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    PublicationOpen Access
    Inhibition of epidermal growth factor receptor suppresses parathyroid hormone-related protein expression in tumours and ameliorates cancer-associated cachexia
    (Wiley, 2022) Department of Molecular Biology and Genetics; Weber, Bahar Zehra Camurdanoğlu; Kır, Serkan; Arabacı, Hilal Dilşad; Department of Molecular Biology and Genetics; College of Engineering; Graduate School of Sciences and Engineering
    Background: lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour-derived parathyroid hormone-related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by Pthlh) gene expression and the impact of this relationship on cancer cachexia. Methods: global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. Pthlh mRNA levels were measured by qRT-PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour-bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour Pthlh mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA-seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of PTHLH and EGFR along with correlation analysis of PTHLH with EGFR and transforming growth factor alpha (TGFA) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to PTHLH expression. Results: expression of EGFR ligands, EGFR itself, and PTHrP co-clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8-fold, P < 0.0005) while EGFR TKIs significantly decrease (90%, P < 0.0005) Pthlh mRNA levels in LLC cells. Pthlh mRNA drops 65-75% (P < 0.0005) in tumours upon treatment of LLC tumour-bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% P < 0.05, 23% P < 0.005, respectively) compared with tumour-bearing control mice. PTHLH is overexpressed in tumours of LUSC (45.8-fold, P < 0.05) and HNSC (17.5-fold, P < 0.05) compared with normal tissue. PTHLH expression correlates with EGFR and its ligand TGFA in both cancers (LUSC: n = 745, R = 0.32, P R = 0.51, P n = 545, R = 0.34, P R = 0.50, P < 0.001, respectively). High PTHLH mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (n = 40, log-rank test, P = 0.0451). Conclusions: epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour-bearing mice.