Heat stress-induced heat shock protein 90 alpha family class A member 1 upregulation stabilizes yes-associated protein through ubiquitination inhibition to boost hepatic cancer radiofrequency hyperthermia resistance.

[BACKGROUND] Hepatocellular carcinoma (HCC) is a prevalent and aggressive form of liver cancer. Understanding how HCC responds to environmental stresses, such as heat stress, is crucial for developing effective treatments. This study explored the relationship between heat shock protein 90 alpha family class A member 1 (HSP90AA1), a key heat shock protein, and the Hippo signaling pathway, particularly yes-associated protein (YAP), in liver cancer cells under heat stress.

[METHODS] Liver cancer cells (HepG2 and Huh7) were subjected to heat stress (43 °C for 30 min) and analyzed for protein expression using Western blotting. Gene knockout and overexpression models were developed in nude mice and liver cancer cells to elucidate the influence of HSP90AA1-YAP interactions on tumorigenesis. Furthermore, functional analysis and advanced molecular biology techniques were employed to uncover the intricate regulatory network governed by HSP90AA1-YAP interactions in HCC.

[RESULTS] Heat stress upregulated heat shock protein expression, notably HSP90AA1, in liver cancer cells. Bioinformatics analyses linked HSP90AA1 to the Hippo-YAP pathway. Moreover, heat stress activated YAP, reducing large tumor suppressor 1 (LATS1)/YAP phosphorylation and increasing YAP levels. Inhibition of YAP weakened this effect, suggesting YAP's role in protecting liver cancer cells from heat stress-induced cytotoxicity. Additionally, silencing HSP90AA1 mitigated YAP pathway activation and enhanced heat stress-induced cytotoxicity in liver cancer cells by inhibiting YAP ubiquitination and stabilizing YAP. In liver cancer xenografts, HSP90AA1 silencing increased sensitivity to radiofrequency hyperthermia (RFH), reducing tumor growth and proliferation.

[CONCLUSIONS] This study revealed that heat stress upregulates HSP90AA1, which stabilizes YAP by inhibiting ubiquitination, activates the YAP pathway, and protects liver cancer cells from cytotoxicity. These findings suggest that HSP90AA1 may be a potential therapeutic target for HCC.