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Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.
Item Metadata only Exceptional response to MEK inhibition in a patient with RAF1-Mutant myxofibrosarcoma: case report and mechanistic overview(Lippincott Williams & Wilkins, 2023) Özgü, E.; Aydin, E.; Adibi, A.; Tokat, Ü.M.; Tutar, O.; Hu, J.; Kurzrock, R.; Demiray, M.; Department of Molecular Biology and Genetics; Demiray, İrem; Undergraduate Student; College of SciencesPublication Metadata only Identification of mitoxantrone as a trail-sensitizing agent for glioblastoma multiforme(Taylor & Francis Inc, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Department of Molecular Biology and Genetics; Şenbabaoğlu, Filiz; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; PhD Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; N/A; N/A; 120842; 184359Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.Publication Metadata only Interferon regulatory factor 4 modulates epigenetic silencing and cancer-critical pathways in melanoma cells(Wiley, 2024) Sobhiafshar, Ulduz; Cakici, Betul; Yilmaz, Erdem; Ayhan, Nalan Yildiz; Hedaya, Laila; Ayhan, Mustafa Can; Yerinde, Cansu; Alankus, Yasemin Begum; Emre, N. C. Tolga; Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Gürkaşlar, Hazal Kübra; Karalar, Elif Nur Fırat; Graduate School of Sciences and Engineering; College of SciencesInterferon regulatory factor 4 (IRF4) was initially identified as a key controller in lymphocyte differentiation and function, and subsequently as a dependency factor and therapy target in lymphocyte-derived cancers. In melanocytes, IRF4 takes part in pigmentation. Although genetic studies have implicated IRF4 in melanoma, how IRF4 functions in melanoma cells has remained largely elusive. Here, we confirmed prevalent IRF4 expression in melanoma and showed that high expression is linked to dependency in cells and mortality in patients. Analysis of genes activated by IRF4 uncovered, as a novel target category, epigenetic silencing factors involved in DNA methylation (DNMT1, DNMT3B, UHRF1) and histone H3K27 methylation (EZH2). Consequently, we show that IRF4 controls the expression of tumour suppressor genes known to be silenced by these epigenetic modifications, for instance cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, the PI3-AKT pathway regulator PTEN, and primary cilium components. Furthermore, IRF4 modulates activity of key downstream oncogenic pathways, such as WNT/beta-catenin and AKT, impacting cell proliferation and survival. Accordingly, IRF4 modifies the effectiveness of pertinent epigenetic drugs on melanoma cells, a finding that encourages further studies towards therapeutic targeting of IRF4 in melanoma. In this study, we showed that high interferon regulatory factor 4 (IRF4) expression is linked to dependency in melanoma cells and mortality in patients. Transcriptomic analysis uncovered epigenetic silencing factors as a novel target category. IRF4 consequently controls the expression of tumour suppressor genes known to be silenced by these epigenetic factors, and the activity of key downstream oncogenic pathways. imagePublication Open Access Metabolic reprogramming in adipose tissue during cancer cachexia(Frontiers, 2022) Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Weber, Bahar Zehra Camurdanoğlu; Arabacı, Hilal Dilşad; Kır, Serkan; Faculty Member; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 274185Cancer 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.Publication Metadata only Mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme(Elsevier, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Department of Molecular Biology and Genetics; Şenbabaoğlu, Fatih; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; Master Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 120842; 184359Background: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, glioblastoma multiforme (GBM). Material and Methods: GBM cell lines U87MG, U373 and non-malignant cell lines BJ fibroblasts and Normal Human Astrocytes were used in in vitro experiments. 1,200 FDA approved drugs containing library was screened as single agents (5 uM) and/or TRAIL (25 ng/ml) in U87MG and U87MGR50. Cell viability was detected by an ATP-based assay after 24−48 hours. Chosen lead, Mitoxantrone was further studied by cell viability assays, proliferation by live cell imaging, apoptotic gene expression levels by qRT-PCR and death receptor and apoptotic protein expression levels by Western Blot. Results: Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Conclusions: Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.Publication Metadata only Mitoxantrone potentiates TRAIL-induced apoptosis in glioblastoma multiforme(Oxford Univ Press, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Department of Molecular Biology and Genetics; Şenbabaoğlu, Filiz; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; PhD Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 120842; 184359Glioblastoma multiforme (GBM) is the most aggressive and frequent type of primary brain tumor with dismal survival rates. As GBM cells suppress apoptosis and evade death, re-activating dormant apoptotic programs with pro-apoptotic ligands or small molecules might be a promising approach. As such, the tumor-selective killing capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential treatment option in GBM. However, many tumor cells are intrinsically resistant and/or acquire resistance to TRAIL. In this study, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in GBM. Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. One drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.Publication Metadata only Overcoming chemoresistance in triple negative breast cancer by bromodomain inhibition(Elsevier Sci Ltd, 2022) Philpott, M.; Cribbs, A.; Oppermann, U.; Onder, T. T.; Department of Molecular Biology and Genetics; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; Bayram, Özlem Yedier; Cingöz, Ahmet; Aksu, Ali Cenk; Değirmenci, Nareg Pınarbaşı; Esin, Beril; Kayabölen, Alişan; Cevatemre, Buse; Ayhan, Ceyda Açılan; Önder, Tuğba Bağcı; Researcher; Researcher; PhD Student; PhD Student; Master Student; PhD Student; Researcher; Faculty Member; Faculty Member; College of Engineering; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 219658; 184359Background: Triple negative breast cancer (TNBC) is an aggressive subtypeofbreastcancerwithpoorprognosis.TNBCcellsdonotexpress receptorsforestrogen,progesteroneorHer2,eliminatingthepossibilityof targetedtherapyapplications.Therefore,current treatmentoptionforTNBC is limitedwithsurgery followedbyconventional chemotherapy.However, acquiredresistancetochemotherapyisamajorchallengethatisassociated withrelapse,whichisdrivenbycoordinatedactionsofgeneticandepigenetic events. MaterialsandMethods:Weaimedtoelucidatetherolesoffullspectrum ofepigeneticmodifiersinmaintenanceandreversionofchemoresistancein TNBC.TogenerateinvitromodelsofchemoresistantTNBC,weexposed3 different TNBC cell lines to escalating doses of taxane (paclitaxel). Transcriptome analysis by RNA-sequencingwere performed to reveal changesthat regulatechemoresistance.Withourcustomepigenome-wide CRISPR-Cas9library(EpigeneticKnock-OutLibrary-EPIKOL)targetingall chromatinreaders,writers,erasersandassociatedproteins,wesystematicallyinterrogatedtherolesofepigeneticmodifiersinchemoresistantTNBC cells.Wealsoconductedmediumscalechemicalscreensutilizingepigenetic probelibrariesinchemoresistantcells. Results:RNAsequencingonpairedsensitiveandchemoresistancecell linesrevealedABCB1upregulationasamajordriverofresistance.Inhibition of themembersofMLLandSWI/SNFcomplexes, aswell as thegenes relatedwithhistoneubiquitinationandacetyl-mark readers re-sensitized chemoresistantcellstopaclitaxel.Amemberof thebromodomainprotein family,BRPF1,cameasacommonhit inourchemical screenaswellas geneticscreens.KnockoutofBRPF1or itschemical inhibitioncompletely abolishedpaclitaxel resistanceandmodulatedABCB1expression. Conclusions:ThroughEPIKOLscreensonchemoresistantTNBCcells coupledwithchemicalscreens,weidentifiednovelepigeneticmodifiersthat arecrucial formaintainingandovercomingdrug resistance.Collectively, thesefindingsprovideabasistodevelopcombinationtherapiestoefficiently killchemoresistantTNBC.Item Metadata only Parathyroid hormone related protein (PTHrP) in patients with pancreatic carcinoma and overt signs of disease progression and host tissue wasting(Elsevier Science Inc, 2023) 0000-0001-8722-9913; Iresjo, Britt-Marie; Lundholm, Kent; Department of Molecular Biology and Genetics; Kır, Serkan; Faculty Member; College of Sciences; 274185Background: Cancer-cachexia is a complex syndrome secondary to physiological mechanisms related to classical hormone and immune alterations, where contributions of neuro-endocrine involvement have been less evalu-ated. Therefore, the aim of our study was to explore relationships between PTHrP and whole body metabolism in patients with progressive pancreatic carcinoma; relevant to "fat tissue browning".Methods: Patient serum samples and clinical information were retrieved from earlier translational projects (1995-2005), at Sahlgrenska University Hospital in Gothenburg. Blood PTHrP levels were determined at Harvard medical School (2014). Patient data included: medical history, clinical laboratory tests, food diaries, resting metabolic expenditure, body composition, exercise capacity, Health-Related Quality of Life (SF-36) and mental disorders (HAD-scales).Results: Serum PTHrP was detectable in 17 % of all samples without significance to tumor stage. PTHrP-negativity at inclusion remained during follow-up. Mean PTHrP concentration was 262 & PLUSMN;274 pg/ml, without sex difference and elevation over time. PTHrP-positive and negative patients experienced similar body weight loss (%) at inclusion, with a trend to deviate at follow ups (16.8 & PLUSMN;8.2% vs. 13.1 & PLUSMN;8.2%, p<0.06), where PTHrP concentrations showed correlations to weight loss, handgrip strength and Karnofsky performance, without difference in exercise capacity. PTHrP-positivity was related to increased whole body fat oxidation (p<0.006-0.01) and reduced carbohydrate oxidation (p<0.01-0.03), independently of peripheral lipolysis. Metabolic alterations in PTHrP-positive patients were related to reduced Health Related Quality of life (SF: p<0.08, MH: p<0.02), and increased anxiety and depression (HAD 1-7: p<0.004; HAD 8-14: p<0.008).Conclusion: Serum PTHrP positivity in patients with pancreatic carcinoma was related to altered whole body oxidative metabolism; perhaps induced by "browning" of fat cells?Item Metadata only PARP inhibitor combinations with high-dose vitamin C in the treatment of Ewing sarcoma: two case reports and mechanistic overview(Sage Publications Ltd, 2023) Adibi, Ashkan; Tokat, Unal Metin; Ozgu, Eylul; Aydin, Esranur; Demiray, Mutlu; Department of Molecular Biology and Genetics; Demiray, İrem; Undergraduate Student; College of SciencesEwing's sarcoma (ES) is a bone and soft tissue tumor that mainly occurs at a young age. The underlying cause of Ewing's sarcoma is the formation of fusion proteins between FET family genes and ETS family genes. Tumors with FET/ETS fusion genes can have defects in the DNA damage response and are sensitive to PARP inhibitors (PARPi). However, several studies have shown that PARPi alone is not sufficient to induce a meaningful antitumor response and that combinations of DNA-damaging agents with PARPi are required to achieve efficacy. Accordingly, preclinical studies have reported dramatic responses to PARPi treatment in combination with DNA-damaging agents such as temozolomide or irinotecan. Similarly, it has been previously reported that by generating reactive oxygen species, high-dose intravenous vitamin C (IVC) can induce DNA damage. This suggests that the combination of IVC with PARPi may increase genotoxic stress and enhance the antitumor response. In addition, unlike chemotherapeutic agents, IVC induces DNA damage selectively in cancer cells, and the side effects are significantly milder than those of chemotherapy. As ETS fusion-positive ES is deficient in faithful DNA repair, partly due to the interaction between ETS fusion products and PARP1, a PARPi plus IVC seems to be a logical and effective combination for the treatment of ETS fusion-positive ES. This paper reports significant responses to IVC (1-1.5 g/kg) in combination with PARPi (olaparib 300 mg BID or talazoparib 1 mg/day) in two patients with metastatic Ewing's sarcoma. The observations highlight an unmet therapeutic need for patients with advanced metastatic ES. The combination of PARPi with a selective DNA-damaging agent was effective in these cases. This case experience suggests that IVC may be incorporated into PARPi-based therapeutic strategies. Further studies are needed to confirm the efficacy of this combination in the treatment of Ewing sarcoma with ETS fusions.