Affiliated Cancer Hospital & institute of Guangzhou Medical University, Guangzhou, 510095, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Adv Sci (Weinh). 2023 Sep;10(27):e2302025. doi: 10.1002/advs.202302025. Epub 2023 Jul 28.
YTH domain family 2 (YTHDF2) is the first identified N6-methyladenosine (m 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 (HSP90β) 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 HSP90β is required for its interaction with STUB1 and YTHDF2. HSP90β 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, HSP90β and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90β is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90β. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC.
YTH 结构域家族 2（YTHDF2）是第一个被鉴定的 N6-甲基腺苷（m A）阅读器，它可以调节 mRNA 的状态。有报道称，过表达的 YTHDF2 促进了癌症的发生；然而，它在肝细胞癌（HCC）中的作用还不清楚。本研究表明，YTHDF2 上调，并可预测 HCC 的不良预后。YTHDF2 的泛素化水平降低导致其上调。此外，热休克蛋白 90β（HSP90β）和 STIP1 同源和 U -box 包含蛋白 1（STUB1）在细胞质中与 YTHDF2 相互作用。在机制上，HSP90β 的大、小中间结构域是其与 STUB1 和 YTHDF2 相互作用所必需的。HSP90β 抑制 STUB1 诱导的 YTHDF2 降解，从而提高 YTHDF2 的表达水平，进一步促进 HCC 的增殖和索拉非尼耐药性。此外，HCC 组织中 HSP90β 和 YTHDF2 上调，而 STUB1 下调。HSP90β 的表达与 YTHDF2 蛋白水平呈正相关，而 STUB1 的表达与 YTHDF2 和 HSP90β 的蛋白水平呈负相关。这些发现加深了对 YTHDF2 如何被调控以驱动 HCC 进展的理解，并为治疗 HCC 提供了潜在的靶点。
