Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Hashizume, Rintaro; Andor, Noemi; Ihara, Yuichiro; Lerner, Robin G.; Gan, Haiyun; Chen, Xiaoyue; Dong, Fang; Huang, Xi; Tom, Maxwell W.; Ngo, Vy; Solomon, David A.; Mueller, Sabine; Paris, Pamela L.; Zhang, Zhiguo; Petritsch, Claudia; Gupta, Nalin; Waldman, Todd; James, C. David

doi:10.1038/nm.3716

Cited by 424 publications

(385 citation statements)

References 21 publications

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“…Because panobinostat was shown to reduce the expression of oncogenes in DIPG cells (e.g., MK167, CCND1), and to increase global H3 acetylation and H3K27 trimethylation, this drug has also been tested in combination with GSK-J4. Consistent with previous findings, 108 the study confirmed that GSK-J4 decreased cell viability in H3K27M DIPG cell cultures, and further demonstrated that panobinostat synergized with GSK-J4 to significantly decrease cell viability in H3K27M mutant DIPG cell cultures. 117 In addition to glioma therapy, the therapeutic potential of HDAC inhibitors has also been investigated in ATRT.…”

Section: Histone Acetyltransferases and Deacetylasessupporting

confidence: 91%

“…Treatment of 2 H3K27M human brainstem tumor xenografts with GSK-J4 increased animal survival and reduced tumor growth but did not achieve the same effect in animals with xenografts containing wild type H3.3. 108 The confirmation of the delivery of GSK-J4 into the pons using HPLC analysis of nontumor-bearing mice further supports the use of GSK-J4 as a potentially clinically effective targeted therapy. 108 Of interest, this compound has a therapeutic potential for T-ALL, which can be driven by oncogenic activation of NOTCH1 signaling, loss-of-function mutations and deletion of the EZH2 and SUZ12 genes, and in which JMJD3 is more highly expressed compared with other types of leukemia.…”

Section: H3k9mtsmentioning

confidence: 73%

“…108 The confirmation of the delivery of GSK-J4 into the pons using HPLC analysis of nontumor-bearing mice further supports the use of GSK-J4 as a potentially clinically effective targeted therapy. 108 Of interest, this compound has a therapeutic potential for T-ALL, which can be driven by oncogenic activation of NOTCH1 signaling, loss-of-function mutations and deletion of the EZH2 and SUZ12 genes, and in which JMJD3 is more highly expressed compared with other types of leukemia. 81,113,114 Indeed, treatment of T-ALL cells with GSK-J4 also resulted in reduced cell proliferation and increased K27M methylation.…”

Section: H3k9mtsmentioning

confidence: 73%

“…108 Both patient-derived cell lines had global hypomethylation of H3K27 compared with the wild type models. Treatment of K27M mutant cells with GSK-J4 resulted in increased K27me2 and K27me3 and a dose-dependent reduction in cell viability and proliferation (Fig.…”

Section: H3k9mtsmentioning

confidence: 96%

“…133 As another example, GSK-J4 brain access has been assessed in murine DIPG models, after being administered to mice by intraperitoneal injection. 108 After brain resection, each brainstem was dissected from the surrounding brain. GSK-J1, the hydrolysis product and activated derivative of GSK-J4 and the most selective KDM inhibitor yet disclosed, 140 was found in all brainstem samples, indicating that the drug entered the brain and accessed the site of brainstem tumor development.…”

Section: Safety and Feasibility Of Epigenetic Targeted Therapymentioning

confidence: 99%

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

Maury

Hashizume

2017

Epigenetics

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Malignancies are characterized by the reprogramming of epigenetic patterns. This reprogramming includes gains or losses in DNA methylation and disruption of normal patterns of covalent histone modifications, which are associated with changes in chromatin remodeling processes. This review will focus on the mechanisms underlying this reprogramming and, specifically, on the role of histone modification in chromatin machinery and the modifications in epigenetic processes occurring in brain cancer, with a specific focus on epigenetic therapies for pediatric brain tumors.

show abstract

Section: Histone Acetyltransferases and Deacetylasessupporting

confidence: 91%

Section: H3k9mtsmentioning

confidence: 73%

Section: H3k9mtsmentioning

confidence: 73%

Section: H3k9mtsmentioning

confidence: 96%

Section: Safety and Feasibility Of Epigenetic Targeted Therapymentioning

confidence: 99%

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

Maury

Hashizume

2017

Epigenetics

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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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Negative regulation of miR‐1275 by H3K27me3 is critical for glial induction of glioblastoma cells

Mai

Liu

et al. 2019

Molecular Oncology

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Activation of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway induces glial differentiation of glioblastoma (GBM) cells, but the mechanism by which microRNA (miRNA) regulate this process remains poorly understood. In this study, by performing miRNA genomics and loss‐ and gain‐of‐function assays in dibutyryl‐cAMP‐treated GBM cells, we identified a critical negative regulator, hsa‐miR‐1275, that modulates a set of genes involved in cancer progression, stem cell maintenance, and cell maturation and differentiation. Additionally, we confirmed that miR‐1275 directly and negatively regulates the protein expression of glial fibrillary acidic protein (GFAP), a marker of mature astrocytes. Of note, tri‐methyl‐histone H3 (Lys27) (H3K27me3), downstream of the PKA/polycomb repressive complex 2 (PRC2) pathway, accounts for the downregulation of miR‐1275. Furthermore, decreased miR‐1275 expression and induction of GFAP expression were also observed in dibutyryl‐cAMP‐treated primary cultured GBM cells. In a patient‐derived glioma stem cell tumor model, a cAMP elevator and an inhibitor of H3K27me3 methyltransferase inhibited tumor growth, induced differentiation, and reduced expression of miR‐1275. In summary, our study shows that epigenetic inhibition of miR‐1275 by the cAMP/PKA/PRC2/H3K27me3 pathway mediates glial induction of GBM cells, providing a new mechanism and novel targets for differentiation‐inducing therapy.

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Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Cited by 424 publications

References 21 publications

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

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

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

Negative regulation of miR‐1275 by H3K27me3 is critical for glial induction of glioblastoma cells

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