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

Abstract

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 dual-target inhibition can reduce the activation of compensatory pathways, such as autophagy, and reduce the possibility of off-target 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.