Epigenetic meets metabolism: novel vulnerabilities to fight cancer.
Epigenetic meets metabolism: novel vulnerabilities to fight cancer.
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DOI：
10.1186/s12964-023-01253-7
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发表时间：
2023-09-21
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组蛋白经历了过多的翻译后修饰(PTM)，调节核小体和染色质的动态，从而决定细胞的命运。一些证据表明，表观遗传改变的积累是触发异常细胞增殖、侵袭、转移和化疗耐药途径的关键驱动力之一。最近，一类新的组蛋白“非酶共价修饰”(NECM)被描述，它与表观基因组景观和代谢重排相关。这些修饰与细胞代谢适合性密切相关，并能够损害染色质结构。在代谢重编程过程中，高代谢通量导致代谢中间产物和/或副产物的积累，这些中间产物和/或副产物能够与组蛋白尾巴反应，改变表观基因组的动态平衡。组蛋白NECM的积聚是一种破坏性的情况，癌细胞通过过度表达能够去除这些修饰并保持组蛋白结构的特殊的“橡皮擦”酶来进行抵消。在这篇综述中，我们探索了成熟的NECM，强调了它们相应的橡皮擦酶的作用。此外，我们提供了一系列针对这些橡皮擦酶的药物，目的是基于对可能选择性靶向治疗的表观生物标志物的识别，提出个性化药物的新途径。视频摘要在线版本包含可在10.1186/s12964-023-01253-7上查阅的补充材料。
Histones undergo a plethora of post-translational modifications (PTMs) that regulate nucleosome and chromatin dynamics and thus dictate cell fate. Several evidences suggest that the accumulation of epigenetic alterations is one of the key driving forces triggering aberrant cellular proliferation, invasion, metastasis and chemoresistance pathways. Recently a novel class of histone “non-enzymatic covalent modifications” (NECMs), correlating epigenome landscape and metabolic rewiring, have been described. These modifications are tightly related to cell metabolic fitness and are able to impair chromatin architecture. During metabolic reprogramming, the high metabolic flux induces the accumulation of metabolic intermediate and/or by-products able to react with histone tails altering epigenome homeostasis. The accumulation of histone NECMs is a damaging condition that cancer cells counteracts by overexpressing peculiar “eraser” enzymes capable of removing these modifications preserving histones architecture. In this review we explored the well-established NECMs, emphasizing the role of their corresponding eraser enzymes. Additionally, we provide a parterre of drugs aiming to target those eraser enzymes with the intent to propose novel routes of personalized medicine based on the identification of epi-biomarkers which might be selectively targeted for therapy. Video Abstract The online version contains supplementary material available at 10.1186/s12964-023-01253-7.
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