Histone H3K27M Mutation in Brain Tumors

El-Hashash, Ahmed

doi:10.1007/978-981-15-8104-5_3

Cited by 13 publications

(11 citation statements)

References 43 publications

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“…H3K27M glioma cells exhibit greater proliferation potential due to the aberrant oncogenic program 176 . Together with RNA pol II and H3K27ac, H3K27M localizes to transcriptionally active regions and can drive SE formation 177,178 . H3K27M inhibits the enzymatic activity of PCR2 through its interaction with the E2H2 subunit, resulting in the loss of H3K27me3 at SE regions 179,180 .…”

Section: Ses In Pediatric Brain Tumorsmentioning

confidence: 99%

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

Zhuang

Teng

et al. 2023

Exp Mol Med

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Transcriptional deregulation, a cancer cell hallmark, is driven by epigenetic abnormalities in the majority of brain tumors, including adult glioblastoma and pediatric brain tumors. Epigenetic abnormalities can activate epigenetic regulatory elements to regulate the expression of oncogenes. Superenhancers (SEs), identified as novel epigenetic regulatory elements, are clusters of enhancers with cell-type specificity that can drive the aberrant transcription of oncogenes and promote tumor initiation and progression. As gene regulators, SEs are involved in tumorigenesis in a variety of tumors, including brain tumors. SEs are susceptible to inhibition by their key components, such as bromodomain protein 4 and cyclin-dependent kinase 7, providing new opportunities for antitumor therapy. In this review, we summarized the characteristics and identification, unique organizational structures, and activation mechanisms of SEs in tumors, as well as the clinical applications related to SEs in tumor therapy and prognostication. Based on a review of the literature, we discussed the relationship between SEs and different brain tumors and potential therapeutic targets, focusing on glioblastoma.

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Section: Ses In Pediatric Brain Tumorsmentioning

confidence: 99%

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

Zhuang

Teng

et al. 2023

Exp Mol Med

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“…Regardless of its aggressiveness and the absence of an effective treatment, DIPG originates in the pons of the brainstem [ 49 ]; however, its five-year survival is <1%, with 90% of children passing away within two years of diagnosis [ 48 , 50 ]. Around 80% of DIPG cases harbor a histone H3K27M mutation, which in turn leads to the loss of H3K27 trimethylation at the lysine residue of histone [ 50 , 51 , 52 ].…”

Section: Different Types Of Pediatric Brain Tumors and Their Molecula...mentioning

confidence: 99%

Molecular Engines, Therapeutic Targets, and Challenges in Pediatric Brain Tumors: A Special Emphasis on Hydrogen Sulfide and RNA-Based Nano-Delivery

Fahmy¹,

Dawoud

Zeinelabdeen

et al. 2022

Cancers

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Pediatric brain tumors represent a formidable challenge in the field of oncology. Pediatric brain tumors are sub-classified into several molecular sub-types, where each one is characterized by an array of hyperactivated oncogenic molecular engines. However, there have been great efforts dedicated to portray the involved signaling pathways driving pediatric brain tumors. Yet, a full understanding of the intertwined oncogenic pathways involved is still obscure. In this review, the authors shed light on novel therapeutic targets tailored for several sub-types of pediatric brain tumors and point out the limitations of such therapeutic approaches. Hydrogen Sulfide (H2S) has recently been cast as an oncogenic driver in several solid malignancies, yet its role in brain tumors is still under investigation. The authors also highlight the possible involvement of H2S in pediatric brain tumors and propose promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumors patients.Abstract: Pediatric primary brain tumors represent a real challenge in the oncology arena. Besides the psychosocial burden, brain tumors are considered one of the most difficult-to-treat malignancies due to their sophisticated cellular and molecular pathophysiology. Notwithstanding the advances in research and the substantial efforts to develop a suitable therapy, a full understanding of the molecular pathways involved in primary brain tumors is still demanded. On the other hand, the physiological nature of the blood–brain barrier (BBB) limits the efficiency of many available treatments, including molecular therapeutic approaches. Hydrogen Sulfide (H2S), as a member of the gasotransmitters family, and its synthesizing machinery have represented promising molecular targets for plentiful cancer types. However, its role in primary brain tumors, generally, and pediatric types, particularly, is barely investigated. In this review, the authors shed the light on the novel role of hydrogen sulfide (H2S) as a prominent player in pediatric brain tumor pathophysiology and its potential as a therapeutic avenue for brain tumors. In addition, the review also focuses on the challenges and opportunities of several molecular targeting approaches and proposes promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumor patients.

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“…In cancer, there are tumors associated with mutations or amplification of genes that code for specific lysine modifications of histones [ 22 , 23 , 24 , 25 ], further supporting their potential role as therapeutic targets ( Figure 2 ). For several members of these enzymes there is evidence pointing to their therapeutic potential, which is still far from being an established treatment and novel preclinical, and later clinical studies are needed to determine their clinical usefulness and identify their specific tumor indication.…”

Section: Epigenetic Chromatin Remodeling As Pharmacological Targetmentioning

confidence: 99%

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Lazo

2022

Cancers

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Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

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Histone H3K27M Mutation in Brain Tumors

Cited by 13 publications

References 43 publications

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

Molecular Engines, Therapeutic Targets, and Challenges in Pediatric Brain Tumors: A Special Emphasis on Hydrogen Sulfide and RNA-Based Nano-Delivery

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

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