Researcher:
Kaplan, Anıl

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Undergraduate Student

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Anıl

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Kaplan

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Kaplan, Anıl

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2014 - 20192

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    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.
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    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.