Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine

Staberg, Mikkel; Michaelsen, Signe Regner; Rasmussen, Rikke; Villingshøj, Mette; Poulsen, Hans Skovgaard; Hamerlik, Petra

doi:10.1007/s13402-016-0301-9

Cited by 53 publications

(36 citation statements)

References 52 publications

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“…Even with treatments involving surgical intervention, irradiation, and chemotherapy, only a fraction of these patients with malignant brain tumor/metastasis survives longer than 2 years after diagnosis (1, 2). Recently, several drugs have shown to target neoplastic cells, which directly modulate the progression of brain tumor (3–5). Brain tumors develop a complex tumor microenvironment, which contributes to the development of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

The roles of microglia macrophages in tumor progression of brain cancer and metastatic disease

Watabe

2017

Front Biosci

125

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Malignant brain tumors and brain metastases are highly aggressive diseases that are often resistant to treatments. Consequently, the current prognosis of patients with brain tumors and metastases is dismal. Activated microglia and macrophages are often observed in close proximity to or within the malignant tumor masses, suggesting that microglia/macrophages play an important role in brain tumor progression. Microglia, being resident macrophages of the central nervous system, form a major component of the brain immune system. They exhibit anti-tumor functions by phagocytosis and the release of cytotoxic factors. However, these microglia/macrophages can be polarized into becoming tumor-supportive and immunosuppressive cells by certain tumor-derived soluble factors, thereby promoting tumor maintenance and progression. The activated microglia/macrophages also participate in the process of tumor angiogenesis, metastasis, dormancy, and relapse. In this review, we discuss the recent literature on the dual roles of microglia/macrophages in brain tumor progression. We have also reviewed the effect of several well-known microglia/macrophages-derived molecules and signals on brain tumor progression and further discussed the potential therapeutic strategies for targeting the pro-tumor and metastatic functions of microglia/macrophages.

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Section: Introductionmentioning

confidence: 99%

The roles of microglia macrophages in tumor progression of brain cancer and metastatic disease

Watabe

2017

Front Biosci

125

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“…The expression levels of the other nine genes were negatively related to OS time in the univariate analysis. HDAC1, one of the most studied histone deacetylases, functions as a powerful tumor promotor and enhances chemoresistance in a variety of cancers [34][35][36][37][38][39]. Our results showed that it was the main regulatory factor in the LAR interaction network and loss of HDAC1 copy number with 1p deletion contributed to a better prognosis in gliomas.…”

Section: Discussionmentioning

confidence: 55%

Multi-omics Prognostic Analysis of Lysine Acetylation Regulators in Glioma

et al. 2020

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Background: Lysine acetylation is a crucial kind of protein modification and is related to the malignant development of various cancers. But their roles in glioma are still unclear and needed concluded comprehensively. Methods: In this study, we comprehensively analyzed the expression levels of 33 lysine acetylation regulators (LARs) and prognostic roles by using public data, including the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). The prognostic roles of LARs were judged by univariate Cox regression. Consensus clustering was applied to result in three stratified glioma subtypes (LA1, 2, and 3) with different clinical outcomes. We also constructed a risk signature for predicting the overall survival of glioma patients by using least absolute shrinkage and selection operator regression (LASSO regression). Besides, copy number variations (CNVs) and single nucleotide polymorphism (SNP) of LARs were also analyzed in our study. Results: We found the mRNA expression levels of most of LARs were dysregulated in gliomas and associated with the prognosis of glioma patients. The risk signature constructed by 14 LARs presented an independent prognostic role in both the CGGA (HR:1.96, 95%CI:1.33-2.90) and TCGA (HR:1.48, 95%CI:1.08-2.03) datasets and robust predictive effects in the ROC curves with all of area under curves more than 0.800. Moreover, the copy number variations of LARs were also significantly related to the prognosis of glioma patients, in which HDAC1 (1p) was one of the oncogenes lost in 1p/19q codeletion events, while SIRT2 (19q) and EP300 (22q) may act as tumor suppressors in gliomas with 19q or 22q deletions, respectively. Conclusion: LARs are potential biomarkers for the malignant progression of gliomas, and our results could be useful for predicting the OS of glioma patients and provide some clues in searching the functions of LARs in glioma progression. Keywords: glioma, lysine acetylation regulator, epigenetic, prognostic signature, biomarker.

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“…The MTT assay (Sigma M‐5655) was employed (Figs F, , A and ) as previously described (Staberg et al ., ). Cells were plated at a density of 1 × 10 4 cells per well in 96‐well plates, transfected with siRNA constructs, or treated with GSK‐J4, lomustine, etoposide, or DMSO.…”

Section: Methodsmentioning

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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Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine

Abstract: From our data we conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM.

Cited by 53 publications

References 52 publications

The roles of microglia macrophages in tumor progression of brain cancer and metastatic disease

The roles of microglia macrophages in tumor progression of brain cancer and metastatic disease

Multi-omics Prognostic Analysis of Lysine Acetylation Regulators in Glioma

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

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