HSP90? Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.

YTH domain family 2 (YTHDF2) is the first identified N6-methyladenosine (m6 A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes ...
in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90?) and STIP1 homology and U-box-containing protein 1 (STUB1) physically interact with YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of HSP90? is required for its interaction with STUB1 and YTHDF2. HSP90? inhibits the STUB1-induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90? and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90? is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90?. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC.
Mesh Terms:
Carcinoma, Hepatocellular, HSP90 Heat-Shock Proteins, Humans, Liver Neoplasms, RNA-Binding Proteins, Sorafenib, Ubiquitin-Protein Ligases, Ubiquitination, Up-Regulation
Adv Sci (Weinh)
Date: Sep. 01, 2023
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