Researcher:
Saraç, Hilal

Profile Picture
ORCID

Job Title

PhD Student

First Name

Hilal

Last Name

Saraç

Name

Name Variants

Saraç, Hilal

Email Address

Birth Date

Filters

2014 - 201942020 - 20221

Advanced Search

Filter by

Settings

Researcher Of Publications: search.filters.isAuthorOfPublication.7b571b6b-2f36-462e-b6b9-d721c859b744

Search Results

Now showing 1 - 5 of 5
  • Placeholder
    PublicationMetadata only
    Epigenetic modifications of androgen receptor signaling in castration resistant prostate cancer (CRPC)
    (Elsevier Sci Ltd, 2014) Saraç, Hilal; Toparlak, Ömer Duhan; Kaplan, Anıl; Ebrahimi, Ayyub A.; Önder, Tuğba Bağcı; Önder, Tamer Tevfik; Lack, Nathan Alan; PhD Student; Other; Undergraduate Student; Researcher; Faculty Member; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; 381072; 184359; 42946; 120842
    Introduction: Prostate cancer is one of the most common forms of cancer in Turkish and European men. For those patients with late-stage prostate cancer, androgen depletion therapy is current standard treatment. While initially successful, almost all patients eventually develop resistance against this treatment. Once the cancer reaches this advanced, progressive form, it is termed castration resistant prostate cancer (CRPC). Whereas the progression mechanisms of CRPC are poorly understood, it has been shown that in CRPC patients, the androgen receptor (AR) is still active despite undetectable androgen levels. Since AR signaling is important in the progression and growth of prostate cancer, understanding how AR mediated signaling occurs in CRPC is critical to more efficient treatment of this recurrent disease. Material and Methods: There are several possible causes for this conversion from androgen-sensitive to androgen-independent prostate cancer. Previous work has demonstrated that epigenetic modifiers such as EZH2 and LSD1 can mediate the sensitization of androgen receptor in CRPC. However, only a small subset of epigenetic modifiers has been characterized. To better understand the role of histone modification on CRPC, we conducted a large scale shRNA screen of epigenetic modifying enzymes to identify those genes that prevent androgen-independent growth. Results and Discussion: From this screen several hit genes have been found that cause a reversion of androgen-independent to androgen-dependent prostate cancer. The shRNA knock-down of these hit genes was confirmed by western blot and qRT-PCR. We are currently characterizing how these epigenetic modifiers affect androgen-receptor mediated signalling. Conclusion: These results will offer new insight into the role of epigenetic modifiers in nuclear receptor signalling.
  • Placeholder
    PublicationMetadata only
    Identification of chemotherapeutic resistant mutations in castration-resistant prostate cancer
    (Elsevier Sci Ltd, 2016) N/A; N/A; N/A; N/A; Özgün, Fatma; Saraç, Hilal; Lack, Nathan Alan; PhD Student; PhD Student; Faculty Member; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; School of Medicine; N/A; N/A; 120842
    N/A
  • Placeholder
    PublicationMetadata only
    Histologically benign PI-RADS 4 and 5 lesions contain cancer-associated epigenetic alterations
    (Wiley, 2022) Sağlıcan, Yeşim; İnce, Ümit; Kılıc, Mert; Vural, Metin; Coşkun, Bilgen; N/A; N/A; N/A; N/A; N/A; Şeref, Ceren; Acar, Ömer; Saraç, Hilal; Esen, Tarık; Lack, Nathan Alan; PhD Student; Faculty Member; PhD Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; School of Medicine; Graduate School of Sciences and Engineering; School of Medicine; School of Medicine; N/A; 237530; N/A; 50536; 120842
    Background: The detection rate of clinically significant prostate cancer has improved with the use of multiparametric magnetic resonance imaging (mpMRI). Yet, even with MRI-guided biopsy 15%-35% of high-risk lesions (Prostate Imaging-Reporting and Data System [PI-RADS] 4 and 5) are histologically benign. It is unclear if these false positives are due to diagnostic/sampling errors or pathophysiological alterations. To better understand this, we tested histologically benign PI-RAD 4 and 5 lesions for common malignant epigenetic alterations. Materials and Methods: MRI-guided in-bore biopsy samples were collected from 45 patients with PI-RADS 4 (n = 31) or 5 (n = 14) lesions. Patients had a median clinical follow-up of 3.8 years. High-risk mpMRI patients were grouped based on their histology into biopsy positive for tumor (BPT; n = 28) or biopsy negative for tumor (BNT; n = 17). From these biopsy samples, DNA methylation of well-known tumor suppressor genes (APC, GSTP1, and RAR beta 2) was quantified. Results: Similar to previous work we observed high rates of promoter methylation at GSTP1 (92.7%), RAR beta 2 (57.3%), and APC (37.8%) in malignant BPT samples but no methylation in benign TURP chips. Interestingly, similar to the malignant samples the BNT biopsies also had increased methylation at the promoter of GSTP1 (78.8%) and RAR beta 2 (34.6%). However, despite these epigenetic alterations none of these BNT patients developed prostate cancer, and those who underwent repeat mpMRI (n = 8) demonstrated either radiological regression or stability. Conclusions: Histologically benign PI-RADS 4 and 5 lesions harbor prostate cancer-associated epigenetic alterations.
  • Thumbnail Image
    PublicationOpen Access
    Determining the origin of synchronous multifocal bladder cancer by exome sequencing
    (BioMed Central, 2015) Özkurt, Ezgi; Demir, Gulfem; Alkan, Can; Somel, Mehmet; N/A; N/A; Esen, Tarık; Lack, Nathan Alan; Acar, Ömer; Saraç, Hilal; Faculty Member; Faculty Member; Faculty Member; PhD Student; School of Medicine; 50536; 120842; 237530; N/A
    Background: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pta urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated snvs were cytosine mutations of tpc* dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that tpc* type mutations occurred 2-5x more often among snvs on the ancestral branches than in the more recent private branches (p < 10-4) suggesting that tpc* mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.
  • 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.