AHSA1 Promotes Proliferation and EMT by Regulating ERK/CALD1 Axis in Hepatocellular Carcinoma

Simple Summary Globally, hepatocellular carcinoma is one of the leading causes of cancer-related death. Activator of HSP90 ATPase activity 1(AHSA1) was reported to be involved in regulating the maturation, stability, and degradation of related cancer-promoting proteins. However, the biological function and regulatory mechanism of AHSA1 in hepatocellular carcinoma were unclearly. In this study, we found AHSA1 was upregulated and associated with poor clinical characteristics and prognosis of hepatocellular carcinoma patients. Moreover, AHSA1 promoted proliferation, metastasis, epithelium-mesenchymal transition of hepatocellular carcinoma both in vitro and in vivo by recruiting ERK1/2 and promoting the phosphorylation and inactivation of CALD1. Taken together, our findings provided a mechanistic insight into the role of AHSA1 in hepatocellular carcinoma progression and implied AHSA1 may be a biomarker and therapeutic target for hepatocellular carcinoma patients. Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. AHSA1 as a chaperone of HSP90 promotes the maturation, stability, and degradation of related cancer-promoting proteins. However, the regulatory mechanism and biological function of AHSA1 in HCC are largely unknown. Actually, we found that AHSA1 was significantly upregulated in HCC tissues and cell lines and was notably correlated with the poor clinical characteristics and prognosis of HCC patients in this study. Furthermore, both in vitro and in vivo, gain- and loss-of-function studies demonstrated that AHSA1 promoted the proliferation, invasion, metastasis, and epithelial-mesenchymal transition (EMT) of HCC. Moreover, the mechanistic study indicated that AHSA1 recruited ERK1/2 and promoted the phosphorylation and inactivation of CALD1, while ERK1/2 phosphorylation inhibitor SCH772984 reversed the role of AHSA1 in the proliferation and EMT of HCC. Furthermore, we demonstrated that the knockdown of CALD1 reversed the inhibition of proliferation and EMT by knocking AHSA1 in HCC. We also illustrated a new molecular mechanism associated with AHSA1 in HCC that was independent of HSP90 and MEK1/2. In summary, AHSA1 may play an oncogenic role in HCC by regulating ERK/CALD1 axis and may serve as a novel therapeutic target for HCC.