HDAC6-HSP90途径介导蛋白折叠和降解调控肿瘤细胞增殖与转移

HDAC6-HSP90 pathway-mediated protein folding and degradation regulates tumor cell proliferation and metastasis

目前认为,关键激酶以及调控蛋白的折叠和降解失调与肿瘤的发生发展密切相关,分子伴侣通过整合蛋白质组(proteome)的折叠与降解机制在维持蛋白稳态中发挥了至关重要的作用.HSP90等伴侣蛋白的异常高表达被认为是恶性肿瘤的标志,通过参与细胞生存以及凋亡途径等关键蛋白的调节,为肿瘤提供了生存优势.HSP90一方面与其他伴侣蛋白相互作用稳定"客户蛋白"的构象,另一方面还能够辅助蛋白酶体途径介导蛋白的降解.最近的研究提示,HSP90的乙酰化等翻译后修饰是维持其功能的关键机制之一.组蛋白去乙酰化酶6(HDAC6)是重要的自噬受体,通过去乙酰化皮层肌动蛋白(cortactin)参与自噬体与溶酶体的融合.目前发现,HDAC6通过降低HSP90的乙酰化水平维持了HSP90分子伴侣的功能,保证客户蛋白的稳定折叠和成熟释放;同时,HDAC6还作为HSP90的客户蛋白,其活性也受到HSP90的调节.因此,进一步研究HSP90与HDAC6的交互作用可能为理解肿瘤细胞的分子伴侣如何协调蛋白折叠与自噬降解机制维持自身生存提供新的思路.本文总结了目前对HSP90以及HDAC6在蛋白折叠以及降解机制中的研究进展,提出HDAC6与HSP90抑制剂联合应用治疗肿瘤,为靶向HSP90-HDAC6途径抑制肿瘤增殖转移提供新的方向与思路.

The folding and degradation of proteins in tumor cells are the key mechanisms maintaining their survival,and functions of the proteins involved are often related to the prevailing tumor resistance.With further scientific research,an increasing number of auxiliary proteins involved in protein folding and degradation have been reported in the literature.The chaperone heat shock protein 90(HSP90)not only promotes protein folding and plays a role in maintaining protein conformation stability but also assists the proteasomal degradation of client proteins.Current research suggests that the function of HSP90 is regulated by post-translational modifications,such as acetylation.Histone deacetylase 6(HDAC6)can inhibit the over-acetylation of HSP90 and maintain the chaperone function of HSP90 to ensure that the client protein of the chaperone HSP90 can be stably folded and maturely released,which creates conditions for tumor survival,proliferation,and metastasis.Furthermore,it can act as the client protein and autophagy receptor of HSP90.It recruits ubiquitinated proteins and deacetylates and modifies autophagy-related proteins,thus playing important roles in protein degradation and autophagy.Recently,studies revealed HDAC6,a client protein of HSP90,which plays an important role in protein degradation,cell autophagy,and maintenance of the activity of HSP90 by preventing its excessive acetylation.By inhibiting HDAC6 to promote HSP90 over-acetylation,it can effectively inhibit the binding between HSP90 and ATP,thereby affecting the folding and degradation of HSP90 on tumor proliferation and metastasis-related proteins.Simultaneously,HDAC inhibitors can help HSP90 bind more closely to its inhibitors.Therefore,HDAC6 and HSP90 inhibitors have also been widely used in related research on tumor treatment,and studies have shown that the combined application of HDAC6 and HSP90 inhibitors has a significant effect on inhibiting tumor proliferation and metastasis.Whether it is to inhibit HDAC6 alone or HSP90 alone,there are deficiencies in cancer treatment.The use of inhibitors alone may lead to the activation of other pathways related to tumor cell proliferation and survival.HDAC6-HSP90 dualtarget inhibition can reduce the activation of compensatory pathways,such as autophagy,and reduce the possibility of offtarget effects of HSP90 inhibitors.In this review,we focus on the crosstalk between HDAC6 and HSP90 to further explain how tumor cells initiate proliferation and metastasis signals by regulating protein folding and degradation mechanisms and discuss the research applications of HDAC6 and HSP90 inhibitors.The advantages and disadvantages are assessed to obtain novel strategies for cancer therapy by targeting the HSP90-HDAC6 pathway.