Wang Ying, Wang Sheng-Yu, Zhang Xu-Hui, Zhao Ming, Hou Chun-Mei, Xu Yuan-Ji, Du Zhi-Yan, Yu Xiao-Dan
Department of Pathology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China.
Biochem Biophys Res Commun. 2007 May 18;356(4):998-1003. doi: 10.1016/j.bbrc.2007.03.076. Epub 2007 Mar 22.
Some pan-histone-deacetylase (HDAC) inhibitors have recently been reported to exert their anti-leukemia effect by inhibiting the activity of class IIB HDAC6, which is the deacetylase of Hsp90 and alpha-tubulin, thereby leading to hyperacetylation of Hsp90, disruption of its chaperone function and apoptosis. In this study, we compared the effect of a class I HDAC inhibitor FK228 with the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on the Hsp90 chaperone function of K562 cells. We demonstrated that, although having a weaker inhibitory effect on HDAC6, FK228 mediated a similar disruption of Hsp90 chaperone function compared to SAHA. Unlike SAHA, FK228 did not mediate hyperacetylation of Hsp90, instead the acetylation of Hsp70 was increased and Bcr-Abl was increasingly associated with Hsp70 rather than Hsp90, forming an unstable complex that promotes Bcr-Abl degradation. These results indicated that FK228 may disrupt the function of Hsp90 indirectly through acetylation of Hsp70 and inhibition of its function.
最近有报道称，一些泛组蛋白去乙酰化酶（HDAC）抑制剂通过抑制IIB类HDAC6的活性发挥其抗白血病作用，HDAC6是Hsp90和α-微管蛋白的去乙酰化酶，从而导致Hsp90的超乙酰化、其伴侣功能的破坏和细胞凋亡。在本研究中，我们比较了I类HDAC抑制剂FK228与泛HDAC抑制剂辛二酰苯胺异羟肟酸（SAHA）对K562细胞Hsp90伴侣功能的影响。我们证明，尽管FK228对HDAC6的抑制作用较弱，但与SAHA相比，它介导了类似的Hsp90伴侣功能破坏。与SAHA不同，FK228没有介导Hsp90的超乙酰化，相反，Hsp70的乙酰化增加，并且Bcr-Abl与Hsp70的结合增加，而不是与Hsp90结合，形成促进Bcr-Abl降解的不稳定复合物。这些结果表明，FK228可能通过Hsp70的乙酰化及其功能抑制间接破坏Hsp90的功能。
