KDM2B, an H3K36-specific demethylase, regulates apoptotic response of GBM cells to TRAIL

Kurt, Ibrahim Cagri; Sur, Ilknur; Kaya, Emre Can; Cingöz, Ahmet; Kazancioglu, Selena; Kahya, Zeynep; Toparlak, Ö. Duhan; Senbabaoglu, Filiz; Kaya, Zeynep; Özyerli, Ezgi; Karahüseyinoğlu, Serçin; Lack, Nathan A.; Gümüş, Zeynep H.; Önder, Tamer T.; Bagcı-Önder, Tugba

doi:10.1038/cddis.2017.288

Cited by 26 publications

(23 citation statements)

References 48 publications

(63 reference statements)

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“…Moreover, a previous study has shown that KDM2B mediates the apoptotic response in GBM cells by activating the apoptotic machinery. 28 …”

Section: Discussionmentioning

confidence: 99%

KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

Wang¹,

Zang²,

Zhang³

et al. 2018

OTT

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BackgroundGliomas are one of the most lethal cancers in the human central nervous system. Despite clinical treatment advancements, the prognosis of patients with glioma remains poor. KDM2B is a histone lysine demethylase, which has been observed in multiple tumors. But the concrete role of KDM2B in gliomas remains to be further illustrated.MethodsThe KDM2B expression in gliomas was detected with immunohistochemistry and Western blot assay. Furthermore, knockdown of KDM2B in U87 and U251 glioma cell lines, the proliferation capacity was evaluated by cell viability assay, colon formation assay and flow cytometry in vitro. Western blot assay was used to analyze the p21, EZH2 and cyclinD1 changes followed by knockdown of KDM2B.ResultsKDM2B was upregulated in tissues of glioma patients, and the expression was correlated to cancer progression. Downregulation of KDM2B in U87 and U251 glioma cell lines inhibited cell proliferation and arrested cell cycle in G0/G1 phase. In addition, silencing KDM2B promoted the upregulation of p21 while reduced the expression of EZH2 and cyclinD1.ConclusionTaken together, our results revealed that KDM2B might influence gliomas growth and act as a novel therapeutic target for glioma patients.

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“…Moreover, a previous study has shown that KDM2B mediates the apoptotic response in GBM cells by activating the apoptotic machinery. 28 …”

Section: Discussionmentioning

confidence: 99%

KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

Wang¹,

Zang²,

Zhang³

et al. 2018

OTT

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“…The shRNA library was described previously [23,73]. pENTR/TEV-D-TOPO-KDM3B plasmid was kindly gifted by Dr Catrine Johansson and Prof. Dr Udo Oppermann.…”

Section: Plasmids Viral Constructionmentioning

confidence: 99%

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

et al. 2019

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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.

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“…This study found local fumarate to inhibit KDM2B activity, which led to enhanced recruitment of NHEJ repair factors to DSBs, more efficient repair and cell survival (Jiang et al ., ). Kurt and coworkers recently proposed a novel role of KDM2B in mediating the repression of proapoptotic proteins (Kurt et al ., ). In line with these observations, our study finds genetic or pharmacologic KDM2B targeting induced DSBs, cleavage of proapoptotic proteins PARP and caspase‐3.…”

Section: Discussionmentioning

confidence: 97%

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

et al. 2018

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Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter‐ and intrapatient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem‐like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells, and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impaired the survival of patient‐derived primary glioblastoma cells through the induction of DNA damage and apoptosis, sensitizing them to chemotherapy. KDM2B loss decreased the GSC pool, which was potentiated by coadministration of chemotherapy. Collectively, our results demonstrate KDM2B is crucial for glioblastoma maintenance, with inhibition causing loss of GSC survival, genomic stability, and chemoresistance.

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KDM2B, an H3K36-specific demethylase, regulates apoptotic response of GBM cells to TRAIL

Cited by 26 publications

References 48 publications

KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

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