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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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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; Gürkaşlar, Hazal Kübra; Karalar, Elif Nur Fırat; Department of Molecular Biology and Genetics; 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 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; 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; Department of Molecular Biology and Genetics; 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; 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; Department of Molecular Biology and Genetics; 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.Publication 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; 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; Department of Molecular Biology and Genetics; 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 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; 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; Department of Molecular Biology and Genetics; 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.