Corresponding Author: Pamela N. Munster, Division of Hematology and Oncology, Department of Medicine, University of California, 1600 Divisadero, Room A719, Box 1711, San Francisco, CA 94143.
Mol Cancer Ther. 2013 Oct;12(10):2078-87. doi: 10.1158/1535-7163.MCT-12-1242. Epub 2013 Aug 12.
Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.
共济失调毛细血管扩张突变基因（ATM）是 DNA 损伤反应的主要调节因子。ATM 促进 BRCA1、CHK2 和 p53 的激活，导致诱导反应基因，如 CDKN1A（p21）、GADD45A 和 RRM2B，促进细胞周期停滞和 DNA 修复。这些反应基因的上调可能有助于癌细胞对遗传毒性治疗产生耐药性。在这里，我们表明组蛋白去乙酰化酶（HDAC）在减轻 ATM 途径对 DNA 损伤的反应中起主要作用。HDAC 抑制降低了 ATM 的激活和表达，并减弱了体外和体内 p53 的激活。选择性耗尽 HDAC1 和 HDAC2 足以调节 ATM 的激活，减少 GADD45A 和 RRM2B 的诱导，并增加对 DNA 链断裂的敏感性。因此，HDAC 酶对 ATM 的调节表明 HDAC1 和 HDAC2 在 DNA 损伤反应中起着至关重要的作用，并且有可能将 ATM 途径用作涉及 HDAC 抑制剂的联合治疗的药效学标志物。
