HSP90 inhibition induces selective destabilization of HDAC6 in a subset of tumor cell types

Histone deacetylases (HDACs) regulate diverse cellular processes through lysine deacetylation and have been implicated in cancer progression and therapy resistance. Histone deacetylase 6 (HDAC6) has been proposed as a client of the molecular chaperone heat shock protein 90 (HSP90); however, the extent and specificity of this interaction remain poorly defined. Here, we examined the contribution of HSP90 activity to the stabilization of HDAC6 and other zinc-dependent HDACs across seven human cancer cell lines of lung, prostate, breast, bone, kidney, and hematologic origin. The cells were treated with pimitespib (TAS-116), a clinically approved HSP90-specific inhibitor. Protein levels were assessed by western blotting. Pimitespib consistently induced the degradation of canonical HSP90 clients Akt and c-Raf in all cell lines. In contrast, HDAC6 exhibited variable responses: its protein level was markedly reduced in A549, PC-3, U-2 OS, and HEK 293T cells but remained stable in MCF7, K-562, and RPMI 8226 cells. HDAC6 mRNA levels were either unchanged or increased, suggesting a posttranscriptional mechanism of destabilization. Other zinc-dependent HDACs (HDAC1-5, 7-9) showed no consistent protein level changes following HSP90 inhibition. These findings identify HDAC6 as a facultative HSP90 client. The selective degradation of HDAC6 contrasts with the uniform destabilization of the canonical client proteins Akt and c-Raf. Our results reveal heterogeneity in HSP90-client interactions and suggest that, unlike HDAC6, other zinc-dependent HDACs are stabilized independently of HSP90.