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组蛋白去乙酰化酶 2 通过刺激 ATM/p53 通路参与人骨肉瘤细胞的 DNA 损伤介导的细胞死亡。

Histone deacetylase 2 is involved in DNA damage-mediated cell death of human osteosarcoma cells through stimulation of the ATM/p53 pathway.

机构信息

Department of Urology The First Hospital of China Medical University Shenyang China.

Department of Reproductive Biology and Transgenic Animal China Medical University Shenyang China.

出版信息

FEBS Open Bio. 2019 Jan 30;9(3):478-489. doi: 10.1002/2211-5463.12585. eCollection 2019 Mar.

DOI:10.1002/2211-5463.12585
PMID:30868056
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6396148/
Abstract

Tumor suppressor p53 is a short-lived nuclear transcription factor, which becomes stabilized and activated in response to a wide variety of cellular stresses. Around 50% of human cancer tissues carry mutations, and certain mutations contribute to chemoresistance. In the present study, we found that histone deacetylase 2 (HDAC2) acts as a co-activator of tumor suppressor p53 and participates in the early molecular events following DNA damage. Anti-cancer drug adriamycin (ADR) treatment induced cell death in -wild-type human osteosarcoma U2OS cells, and this was accompanied by a remarkable accumulation of p53 and γH2AX. gene silencing significantly decreased the sensitivity of U2OS cells to ADR and attenuated p53-dependent DNA damage responses, such as ADR-mediated phosphorylation of ataxia telangiectasia mutated (ATM) and p53, as well as accumulation of γH2AX and cleaved poly (ADP-ribose) polymerase. However, knockdown had a marginal effect on -null human lung cancer H1299 cells following ADR exposure. In contrast, forced expression of HA-HDAC2 promoted cell death and stimulated the transcriptional activity of p53. Moreover, p53 and HDAC2 were found to co-precipitate with ATM. Together, our present results strongly suggest that the p53-HDAC2 axis plays a vital role in the regulation of the DNA damage response and also contributes to chemosensitivity of cancer cells.

摘要

肿瘤抑制因子 p53 是一种短寿命的核转录因子，它会在应对各种细胞应激时变得稳定和激活。大约 50%的人类癌症组织携带 突变，某些 突变有助于化疗耐药性。在本研究中，我们发现组蛋白去乙酰化酶 2 (HDAC2) 作为肿瘤抑制因子 p53 的共激活因子发挥作用，并参与 DNA 损伤后的早期分子事件。抗癌药物阿霉素 (ADR) 处理诱导野生型人骨肉瘤 U2OS 细胞死亡，同时 p53 和 γH2AX 显著积累。 基因沉默显著降低了 U2OS 细胞对 ADR 的敏感性，并减弱了 p53 依赖性的 DNA 损伤反应，如 ADR 介导的共济失调毛细血管扩张突变 (ATM) 和 p53 的磷酸化，以及 γH2AX 和聚（ADP-核糖）聚合酶的切割积累。然而，ADR 暴露后， 基因沉默对 -null 人肺癌 H1299 细胞的影响微不足道。相比之下，HA-HDAC2 的强制表达促进细胞死亡并刺激 p53 的转录活性。此外，还发现 p53 和 HDAC2 与 ATM 共沉淀。总之，我们目前的结果强烈表明，p53-HDAC2 轴在 DNA 损伤反应的调节中起着至关重要的作用，并且有助于癌细胞的化疗敏感性。

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