Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth
Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth
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DOI：
10.1038/s41586-018-0387-5
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发表时间：
2018-08-09
期刊：
影响因子：
64.8
通讯作者：
Thomas, Tim
中科院分区：
文献类型：
--
作者：
Baell, Jonathan B.;Leaver, David J.;Thomas, Tim
赖氨酸乙酰转移酶（KAT）对组蛋白的乙酰化对染色质的组织和功能至关重要（1）。在编码MYST家族KAT（KAT 5-KAT 8）的基因中，有致癌基因KAT 6A（也称为MOZ）和KAT 6 B（也称为MORF和QKF）（2，3）。KAT 6A在正常造血干细胞中具有重要作用（4-6），并且是导致急性髓性白血病的复发性染色体易位的靶点（7，8）。类似地，KAT 6 B中的染色体易位已在多种癌症中被鉴定（8）。KAT 6A通过调节CDKN 2A基因座的抑制子来抑制细胞衰老（9，10），这是一种需要其KAT活性的功能（10）。KAT 6A的一个等位基因的缺失将MYC诱导的淋巴瘤小鼠的中位生存期从105天延长至413天（11）。这些发现表明，抑制KAT 6A和KAT 6 B可能会为癌症提供治疗益处。在这里，我们提出了KAT 6A和KAT 6 B的高效选择性抑制剂，表示为WM-8014和WM-1119。生物化学和结构研究表明，这些化合物是乙酰辅酶A的可逆竞争者，并抑制MYST催化的组蛋白乙酰化。WM-8014和WM-1119诱导细胞周期退出和细胞衰老而不引起DNA损伤。衰老是INK 4A/ARF依赖性的，并伴随着基因表达的变化，这是KAT 6A功能丧失的典型表现。WM-8014在体外和肝细胞癌的斑马鱼模型中增强癌基因诱导的衰老。WM-1119具有增加的生物利用度，可阻止小鼠淋巴瘤的进展。我们预计，这类抑制剂将有助于加速靶向组蛋白乙酰化调控的基因转录的治疗方法的发展。
Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function(1). Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)(2,3). KAT6A has essential roles in normal haematopoietic stem cells(4-6) and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia(7,8). Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers(8). KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus(9,10), a function that requires its KAT activity(10). Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days(11). These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.