Saha Nirmalya, Muntean Andrew G
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States of America.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States of America.
Biochim Biophys Acta Rev Cancer. 2021 Jan;1875(1):188498. doi: 10.1016/j.bbcan.2020.188498. Epub 2020 Dec 26.
Growing evidence implicates histone H3 lysine 9 methylation in tumorigenesis. The SUV family of H3K9 methyltransferases, which include G9a, GLP, SETDB1, SETDB2, SUV39H1 and SUV39H2 deposit H3K9me1/2/3 marks at euchromatic and heterochromatic regions, catalyzed by their conserved SET domain. In cancer, this family of enzymes can be deregulated by genomic alterations and transcriptional mis-expression leading to alteration of transcriptional programs. In solid and hematological malignancies, studies have uncovered pro-oncogenic roles for several H3K9 methyltransferases and accordingly, small molecule inhibitors are being tested as potential therapies. However, emerging evidence demonstrate onco-suppressive roles for these enzymes in cancer development as well. Here, we review the role H3K9 methyltransferases play in tumorigenesis focusing on gene targets and biological pathways affected due to misregulation of these enzymes. We also discuss molecular mechanisms regulating H3K9 methyltransferases and their influence on cancer. Finally, we describe the impact of H3K9 methylation on therapy induced resistance in carcinoma. Converging evidence point to multi-faceted roles for H3K9 methyltransferases in development and cancer that encourages a deeper understanding of these enzymes to inform novel therapy.
越来越多的证据表明组蛋白H3赖氨酸9甲基化与肿瘤发生有关。H3K9甲基转移酶的SUV家族，包括G9a、GLP、SETDB1、SETDB2、SUV39H1和SUV39H2，通过其保守的SET结构域，在常染色质和异染色质区域沉积H3K9me1/2/3标记。在癌症中，该酶家族可因基因组改变和转录错误表达而失调，导致转录程序改变。在实体瘤和血液系统恶性肿瘤中，研究发现几种H3K9甲基转移酶具有促癌作用，因此，小分子抑制剂正在作为潜在疗法进行测试。然而，新出现的证据也表明这些酶在癌症发展中也具有抑癌作用。在这里，我们综述了H3K9甲基转移酶在肿瘤发生中的作用，重点关注因这些酶的调控异常而受影响的基因靶点和生物学途径。我们还讨论了调节H3K9甲基转移酶的分子机制及其对癌症的影响。最后，我们描述了H3K9甲基化对癌症治疗诱导耐药性的影响。越来越多的证据表明，H3K9甲基转移酶在发育和癌症中具有多方面的作用，这鼓励我们更深入地了解这些酶，为新的治疗方法提供依据。
