Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas

Chung, CH; Sweha, Stefan; Pratt, Drew; Tamrazi, Benita; Panwalkar, Pooja; Banda, Adam; Bayliss, Jill; Hawes, Debra; Yang, Fusheng; Lee, Ho‐Joon; Shan, Mengrou; Cieślik, Marcin; Qin, Tingting; Werner, Christian K.; Wahl, Daniel R.; Lyssiotis, Costas A.; Bian, Zhiguo; Shotwell, J. Brad; Yadav, Viveka Nand; Koschmann, Carl; Chinnaiyan, Arul M.; Blüml, Stefan; Judkins, Alexander R.; Venneti, Sriram

doi:10.1016/j.ccell.2020.07.008

Cited by 117 publications

(121 citation statements)

References 47 publications

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“… 13–15 This H3.3K27M-mutant glioma exhibits epigenetic modifications, such as global loss of H3K27 trimethylation (H3K27me3) and reciprocal gain of H3K27 acetylation (H3K27ac). 16 , 17 H3.3K27M mutation in DIPGs also enhances glycolysis and tricarboxylic acid (TCA) cycle metabolism to produce 2-Oxoglutaric acid (also referred to α-KG). 17 However, it is unknown if these epigenetic and metabolic changes link to the diffuse invasion phenotype.…”

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confidence: 99%

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Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Miyai

Kanayama

Hyodo

et al. 2020

Neuro-Oncology Advances

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Background Gliomas typically escape surgical resection and recur due to their “diffusion invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed two key features of the “diffuse invasion” phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. Methods We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffusion invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. Results Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, i.e., attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. Conclusions Targeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.

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confidence: 99%

“… 16 , 17 H3.3K27M mutation in DIPGs also enhances glycolysis and tricarboxylic acid (TCA) cycle metabolism to produce 2-Oxoglutaric acid (also referred to α-KG). 17 However, it is unknown if these epigenetic and metabolic changes link to the diffuse invasion phenotype.…”

mentioning

confidence: 99%

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Miyai

Kanayama

Hyodo

et al. 2020

Neuro-Oncology Advances

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“…Emerging evidence has linked epigenetics and metabolomics to plasticity and intratumor heterogeneity in brain tumors [ 97 – 100 ]. Specifically in DIPGs, recent studies have found that metabolic reprogramming contributes to the pathogenesis of H3.3K27M DIPGs, primarily by utilizing alpha-ketoglutarate to maintain a preferred epigenetic state of low H3K27me3 [ 97 ]. Furthermore, they also show that H3.3K27M cells show intratumoral heterogeneity in their usage of glucose or glutamine to regulate global H3K27me3 with dependence on one or both pathways [ 97 ].…”

Section: Novel Therapeutic Avenuesmentioning

confidence: 99%

“…Specifically in DIPGs, recent studies have found that metabolic reprogramming contributes to the pathogenesis of H3.3K27M DIPGs, primarily by utilizing alpha-ketoglutarate to maintain a preferred epigenetic state of low H3K27me3 [ 97 ]. Furthermore, they also show that H3.3K27M cells show intratumoral heterogeneity in their usage of glucose or glutamine to regulate global H3K27me3 with dependence on one or both pathways [ 97 ]. In return, the metabolic regulation of global H3K27me3 leads to heterogeneous dependencies on glutamate dehydrogenase, hexokinase 2, and wild-type isocitrate dehydrogenase 1 (IDH1), which are possible therapeutic targets.…”

Section: Novel Therapeutic Avenuesmentioning

confidence: 99%

Diffuse intrinsic pontine glioma: current insights and future directions

et al. 2021

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Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor–related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

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“…A recent study published in Cancer Cell by Chan Chung and colleagues demonstrated that H3.3K27M mutation in diffuse intrinsic pontine gliomas (DIPGs) potentiated glycolysis, tricarboxylic acid cycle, and glutaminolysis metabolism with upregulated alpha-ketoglutarate (α-KG), which contributed to sustain an epigenetic status marked by H3K27me3 deficiency and that interruption of these metabolic/epigenetic pathways represented a promising strategy for the treatment of DIPGs, as reprted by Chung, C. et al 1 H3K27M, which refers to that the methionine replaces lysine at site 27 in histone H3-H3F3A and HIST1H3B/C (collectively H3K27M), 1 takes place in more than 80% of diffuse intrinsic pontine gliomas (DIPGs). 2 H3K27M mutations account for a general H3K27me3 deficiency through varied mechanisms, such as its aberrant interactions with PRC2.…”

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confidence: 99%

Targeting metabolic/epigenetic pathways: a potential strategy for cancer therapy in diffuse intrinsic pontine gliomas

Zhao

Miao

2020

Sig Transduct Target Ther

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Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas

Cited by 117 publications

References 47 publications

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Diffuse intrinsic pontine glioma: current insights and future directions

Targeting metabolic/epigenetic pathways: a potential strategy for cancer therapy in diffuse intrinsic pontine gliomas

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