Department of Oncology Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Oncogene. 2010 Apr 15;29(15):2192-204. doi: 10.1038/onc.2009.505. Epub 2010 Feb 1.
Various inhibitors of histone deacetylase (HDAC) activity can sensitize drug resistant cancer cells to chemotherapeutic agents. However, the mechanisms underlying such effects of distinct HDAC inhibitors (HDACi) remain poorly understood. Here we show that both the HDACi trichostatin A and valproic acid induced a sensitization of multidrug-resistant cancer cells to the topoisomerase II inhibitor etoposide/VP16. This effect was associated with increased acetylation of certain lysines on histones H3 and H4, including lysine 16 on histone H4 (H4K16). Overexpression of the histone acetyltransferase hMOF, known to target H4K16, was sufficient to mimic HDACi treatment on sensitization and H4K16 acetylation, and importantly, small-interfering RNA (siRNA)-mediated knockdown of hMOF abolished the HDACi-mediated sensitizing effects as well as the increase in H4K16 acetylation. Conversely, siRNA-mediated knockdown of the H4K16 deacetylase SIRT1 mimicked HDACi treatment whereas overexpression of SIRT1 abolished H4K16 acetylation and significantly reduced the sensitizing effects of HDACi. Interestingly, the effects of hMOF on H4K16 acetylation and sensitization to the topoisomerase II inhibitor could be directly counteracted by exogenous expression of increasing amounts of SIRT1 and vice versa. Our study results suggest that hMOF and SIRT1 activities are critical parameters in HDACi-mediated sensitization of multidrug-resistant cancer cells to topoisomerase II inhibitor and increased H4K16 acetylation.
各种组蛋白去乙酰化酶（HDAC）活性抑制剂可使耐药癌细胞对化疗药物敏感。然而，不同 HDAC 抑制剂（HDACi）产生这种作用的机制仍不清楚。我们的研究表明，HDACi 曲古抑菌素 A 和丙戊酸均能诱导多药耐药癌细胞对拓扑异构酶 II 抑制剂依托泊苷/VP16 敏感。这种作用与组蛋白 H3 和 H4 上某些赖氨酸（包括组蛋白 H4 的赖氨酸 16 [H4K16]）的乙酰化增加有关。已知靶向 H4K16 的组蛋白乙酰转移酶 hMOF 的过表达足以模拟 HDACi 处理对敏感性和 H4K16 乙酰化的影响，重要的是，小干扰 RNA（siRNA）介导的 hMOF 敲低可消除 HDACi 介导的增敏作用以及 H4K16 乙酰化的增加。相反，siRNA 介导的 H4K16 去乙酰化酶 SIRT1 的敲低模拟了 HDACi 处理，而过表达 SIRT1 则消除了 H4K16 乙酰化并显著降低了 HDACi 的增敏作用。有趣的是，hMOF 对 H4K16 乙酰化和对拓扑异构酶 II 抑制剂的敏感性的影响可通过外源性表达越来越多的 SIRT1 直接抵消，反之亦然。我们的研究结果表明，hMOF 和 SIRT1 的活性是 HDACi 介导的多药耐药癌细胞对拓扑异构酶 II 抑制剂增敏和 H4K16 乙酰化增加的关键参数。
