Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Maury, Eléonore; Hashizume, Rintaro

doi:10.1080/15592294.2016.1278095

Cited by 39 publications

(41 citation statements)

References 145 publications

(221 reference statements)

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“…We have previously shown that inhibition of the H3K27 demethylase JMJD3 by GSK-J4 acts to restore K27 methylation in DIPG cells (10). Increased H3K27 methylation promotes heterochromatin, which is transcriptionally silent and decreases gene expression (27). In our current study, GSK-J4-mediated H3K27 methylation significantly decreases DNA accessibility at both promoter and distal binding sites ( Supplementary Fig.…”

Section: Discussionsupporting

confidence: 58%

“…The mutant protein sequesters and functionally inactivates EZH2, a catalytic subunit of the K27 histone methyltransferase, polycomb repressive complex 2 (PRC2), leading to a dramatic reduction in global methylation at K27 residues in the K27M DIPG (7,8). This reduction in H3K27 methylation leads to opening of the chromatin providing access for active transcription (26,27). We have previously shown that inhibition of the H3K27 demethylase JMJD3 by GSK-J4 acts to restore K27 methylation in DIPG cells (10).…”

Section: Discussionmentioning

confidence: 99%

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Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma

Katagi

Louis

Unruh

et al. 2019

Clinical Cancer Research

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Purpose: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiationinduced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers gH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. Results: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of gH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. Conclusions: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma

Katagi

Louis

Unruh

et al. 2019

Clinical Cancer Research

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“…The molecular mechanisms underlying REST-dependent upregulation of GREM-1 is a subject of ongoing investigation. REST is associated with a number of chromatin remodeling enzymes, whose activity can be inhibited by drugs that are currently in use in the clinic or are being investigated in pre-clinical studies [ 5 , 92 – 94 ]. These agents may have applications in the treatment of REST-expressing DIPGs in the future.…”

Section: Discussionmentioning

confidence: 99%

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

et al. 2017

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Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities.

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“…Several members from the chromatin-remodeling families are known to be mutated in human malignancies, raising the possibility that abnormal activities of chromatin remodeling may be the driving force for tumor initiation and progression [31,75]. In brain tumors, genetic defects of the enzymes which are involved in the chromatin remodeling are reported to be the hallmark aberration in some tumor types, notably as driver mutations in histone H3.3 and chromatin remodeling genes in pediatric GBM [58,70].…”

Section: Chromatin Remodelersmentioning

confidence: 99%

Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review

Masui

Cavenee

Mischel

et al. 2020

Acta Histochem. Cytochem.

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Cancer is widely considered to be a set of genetic diseases that are currently classified by tissue and cell type of origin and, increasingly, by its molecular characteristics. This latter aspect is based primarily upon oncogene gains, tumor suppressor losses, and associated transcriptional profiles. However, cancers are also characterized by profound alterations in cellular metabolism and epigenetic landscape. It is particularly noteworthy that cancercausing genomic defects not only activate cell cycle progression, but regulate the opportunistic uptake and utilization of nutrients, effectively enabling tumors to maximize growth and drug resistance in changing tissue and systemic microenvironments. Shifts in chromatin architecture are central to this dynamic behavior. Further, changes in nutrient uptake and utilization directly affect chromatin structure. In this review, we describe a set of recent discoveries of metabolic and epigenetic reprogramming in cancer, and especially focus on the genomically well-characterized brain tumor, glioblastoma. Further, we discuss a new mode of metabolic regulation driven by epigenetic mechanisms, that enables cancer cells to autonomously activate iron metabolism for their survival. Together, these underscore the integration of genetic mutations with metabolic reprogramming and epigenetic shifts in cancer, suggesting a new means to identifying patient subsets suitable for specific precision therapeutics.

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Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Cited by 39 publications

References 145 publications

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma

REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review

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