Current Opinion in Pharmacology最新文献

英文中文

Oncohistone-sculpted epigenetic mechanisms in pediatric brain cancer 儿童脑癌肿瘤组蛋白雕刻的表观遗传机制。

IF 4 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-01-09 DOI: 10.1016/j.coph.2025.102505

Deo Prakash Pandey , Kumar Somyajit

Chromatin dynamics, involving reversible changes in chromatin structure, shape key cellular processes and genomic integrity during development and proliferation, with disruptions leading to cancer. Histones, core components of chromatin and substrates for chromatin-modifying enzymes, play crucial roles in oncogenesis when misregulated or mutated. This is particularly pronounced in pediatric hind brain cancers, some of which are driven primarily by the oncohistone H3K27M and the recently identified oncohistone-mimic protein CXorf67/EZHIP. Notably, H3K27M and EZHIP-driven cancers exhibit low mutation burdens, highlighting the enigmatic role of non-mutational epigenetic reprogramming in oncogenesis beyond traditional paradigms of oncogene activation and tumor suppressor loss. Here, we review the impact of H3K27M and EZHIP-driven cancer mechanisms on chromatin and transcriptional dysregulation leading to aberrant cell fate determination, and their potential influence beyond gene activity, affecting broader cellular pathways. Illuminating these mechanisms is crucial for advancing treatment options for pediatric brain cancers, where therapeutic regimens are poorly defined.

染色质动力学，涉及染色质结构的可逆变化，在发育和增殖过程中塑造关键的细胞过程和基因组完整性，破坏导致癌症。组蛋白是染色质的核心成分和染色质修饰酶的底物，当其被错误调节或突变时，在肿瘤发生中起着至关重要的作用。这在儿童后脑癌中尤为明显，其中一些主要由癌组蛋白H3K27M和最近发现的癌组蛋白模拟蛋白xorf67 /EZHIP驱动。值得注意的是，H3K27M和ezhip驱动的癌症表现出较低的突变负担，突出了非突变表观遗传重编程在肿瘤发生中的神秘作用，超越了传统的癌基因激活和肿瘤抑制因子丧失的范式。在这里，我们回顾了H3K27M和ezhip驱动的癌症机制对染色质和转录失调的影响，导致异常的细胞命运决定，以及它们在基因活性之外的潜在影响，影响更广泛的细胞途径。阐明这些机制对于推进儿童脑癌的治疗方案至关重要，因为儿童脑癌的治疗方案定义不清。

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