IIRC-1, Laboratory of Glycation Biology and Metabolic Disorder, Department of Biosciences, Faculty of Sciences, Integral University, Lucknow, 226026, India.
Department of Public Health, College of Applied Medical Sciences, King Faisal University, Al Ahsa, 31982, Saudi Arabia.
Semin Cancer Biol. 2022 Aug;83:543-555. doi: 10.1016/j.semcancer.2020.11.019. Epub 2020 Dec 2.
The non-enzymatic glycosylation or non-enzymatic covalent modifications (NECMs) or glycation of cellular proteins result in the generation and accumulation of advanced glycation end products (AGEs) that are associated with the epigenetics of cancer. Epigenetic modifications are inheritable changes without alterations in the sequences of DNA. Glycation-mediated epigenetic mechanisms change the accessibility of transcriptional factors to DNA via rearrangement or modification in the chromatin structure and collaborate with gene regulation in the pathogenesis of cancer. Epigenetic mechanisms play a critical role in sustaining the tissue-specific gene expression. Distraction from normal epigenetic mechanism results in alteration of gene function, initiation and progression of cancer, and cellular malignant transformation. Epigenetic modifications on DNA and histones control enzymatic expressions of corresponding metabolic pathways, which in turn influence epigenetic regulation. Glycation of histones due to persistent hyperglycemia results in histone-histone and histone-DNA cross-linking in chromatin by compromising the electrostatic interactions, that affect the dynamic architecture of chromatin. Histone proteins are highly prone to glycation due to their basic nature and long half-lives, but the exact role of histone glycation in the epigenetics of cancer is still in the veil. However, recent studies have suggested the role of histone glycation mediated epigenetic modifications that affect cellular functioning by altering the gene expressions of related metabolic pathways. Moreover, dicarbonyls-induced NECMs of histones perturb the architecture of chromatin and transcription of genes via multiple mechanisms. Contrary to the genetic causes of cancer, a possible reversal of glycation-mediated epigenetic modifications might open a new realm for therapeutic interventions. In this review, we have portrayed a mechanistic link between histone glycation and cancer epigenetics.
细胞蛋白质的非酶糖基化或非酶共价修饰（NECM）或糖基化导致高级糖基化终产物（AGEs）的产生和积累，这些产物与癌症的表观遗传学有关。表观遗传修饰是指在不改变 DNA 序列的情况下可遗传的变化。糖基化介导的表观遗传机制通过染色质结构的重排或修饰改变转录因子与 DNA 的可及性，并与癌症发病机制中的基因调控协同作用。表观遗传机制在维持组织特异性基因表达中起着关键作用。正常表观遗传机制的偏离导致基因功能的改变、癌症的起始和进展以及细胞恶性转化。DNA 和组蛋白上的表观遗传修饰控制相应代谢途径的酶表达，这反过来又影响表观遗传调控。持续高血糖导致组蛋白糖化，通过破坏静电相互作用，在染色质中导致组蛋白-组蛋白和组蛋白-DNA 交联，从而影响染色质的动态结构。由于其碱性性质和长半衰期，组蛋白极易发生糖化，但组蛋白糖化在癌症表观遗传学中的确切作用仍不清楚。然而，最近的研究表明，组蛋白糖化介导的表观遗传修饰通过改变相关代谢途径的基因表达，影响细胞功能。此外，二羰基化合物诱导的组蛋白 NECM 通过多种机制扰乱染色质结构和基因转录。与癌症的遗传原因相反，糖基化介导的表观遗传修饰的可能逆转可能为治疗干预开辟新的领域。在这篇综述中，我们描绘了组蛋白糖化与癌症表观遗传学之间的机制联系。
