Acetylation plays an important role in regulating the chaperone activity of heat shock protein 90 (Hsp90) during malignant transformation through the stabilization and conformational maturation of oncogenic proteins. However, the functional acetylation sites, potential anticancer drug targets, are still emerging. We found that acetylation at K292 in Hsp90α is critical for the development and treatment of breast cancer. Acetylation at K292 not only augments the affinity of Hsp90 to ATP, cochaperones, and client proteins but it also promotes cancer cell colony formation, migration, and invasion in vitro as well as tumor growth in vivo. Importantly, K292‐acetylated Hsp90 has been validated as an exciting anticancer drug target by interfering with the complex formation between K292‐acetylated Hsp90 and cochaperone Cdc37, leading to diminishment of kinase client maturation and proteasome‐dependent degradation of kinase substrates. Furthermore, we showed that simvastatin prevented, whereas LBH589 promoted, the progression of Hsp90 chaperone cycling and client maturation, resulting in an increment of cell apoptosis by the combination of simvastatin and LBH589 in a mouse xenograft model. These data suggest that simvastatin is a novel Hsp90 inhibitor to disrupt the formation of the K292‐acetylated Hsp90/Cdc37 complex in triple‐negative breast cancer cells. The combination of simvastatin with LBH589 could be used as a novel therapeutic strategy for triple‐negative breast cancer.

Prostate cancer (PCa) is one of the most common cancers in males and particularly tends to metastasize to bone. Currently, metastatic bone disease is incurable, and new therapies need to be developed. Our study aims to determine the role of miR‐127‐3p in PCa metastasis to bone. The results demonstrate that miR‐127‐3p is markedly reduced in bone metastasis‐positive PCa tissues relative to that in bone metastasis‐negative PCa tissues. Furthermore, overexpressing miR‐127‐3p inhibits PCa cell invasion and migration in vitro by targeting the proteasome β‐subunit PSMB5. Moreover, CCCTC‐binding factor (CTCF) transcriptionally inhibits miR‐127‐3p by interacting with the miR‐127‐3p promoter. Collectively, this study uncovers a novel mechanism of the CTCF/miR‐127‐3p/PSMB5 axis in promoting PCa bone metastasis, indicating that miR‐127‐3p could function as a promising therapeutic target against bone metastasis.

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