Reed Lauren, Abraham Janak, Patel Shay, Dhar Shilpa S
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Biology (Basel). 2024 Dec 3;13(12):1008. doi: 10.3390/biology13121008.
Histone methyltransferases (HMTs) and histone demethylases (HDMs) are critical enzymes that regulate chromatin dynamics and gene expression through the addition and removal of methyl groups on histone proteins. HMTs, such as PRC2 and SETD2, are involved in the trimethylation of histone H3 at lysine 27 and lysine 36, influencing gene silencing and activation. Dysregulation of these enzymes often leads to abnormal gene expression and contributes to tumorigenesis. In contrast, HDMs including KDM7A and KDM2A reverse these methylation marks, and their dysfunction can drive disease progression. In cancer, the aberrant activity of specific HMTs and HDMs can lead to the silencing of tumor suppressor genes or the activation of oncogenes, facilitating tumor progression and resistance to therapy. Conversely, in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), disruptions in histone methylation dynamics are associated with neuronal loss, altered gene expression, and disease progression. We aimed to comprehend the odd activity of HMTs and HDMs and how they contribute to disease pathogenesis, highlighting their potential as therapeutic targets. By advancing our understanding of these epigenetic regulators, this review provides new insights into their roles in cancer and neurodegenerative diseases, offering a foundation for future research.
组蛋白甲基转移酶(HMTs)和组蛋白去甲基化酶(HDMs)是关键酶,它们通过在组蛋白上添加和去除甲基基团来调节染色质动态和基因表达。HMTs,如多梳抑制复合物2(PRC2)和SET结构域蛋白2(SETD2),参与组蛋白H3赖氨酸27和赖氨酸36的三甲基化,影响基因沉默和激活。这些酶的失调通常会导致基因表达异常,并促进肿瘤发生。相比之下,包括赖氨酸特异性去甲基化酶7A(KDM7A)和赖氨酸特异性去甲基化酶2A(KDM2A)在内的HDMs会逆转这些甲基化标记,它们的功能障碍会推动疾病进展。在癌症中,特定HMTs和HDMs的异常活性会导致抑癌基因沉默或癌基因激活,促进肿瘤进展和对治疗的抵抗。相反,在神经退行性疾病中,如阿尔茨海默病(AD)、帕金森病(PD)和亨廷顿病(HD),组蛋白甲基化动态的破坏与神经元丢失、基因表达改变和疾病进展有关。我们旨在了解HMTs和HDMs的异常活性以及它们如何促成疾病发病机制,突出它们作为治疗靶点的潜力。通过增进我们对这些表观遗传调节因子的理解,本综述为它们在癌症和神经退行性疾病中的作用提供了新见解,为未来研究奠定了基础。