HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.
HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.
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DOI：
10.1002/advs.202302025
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发表时间：
2023-09
期刊：
影响因子：
15.1
通讯作者：
Huang, Hongbiao
中科院分区：
文献类型：
--
作者：
Liao, Yuning;Liu, Yuan;Yu, Cuifu;Lei, Qiucheng;Cheng, Ji;Kong, Weiyao;Yu, Yuanhui;Zhuang, Xuefen;Sun, Wenshuang;Yin, Shusha;Cai, Gengxi;Huang, Hongbiao
YTH结构域家族2（YTHDF 2）是第一个被鉴定的调节mRNA状态的N6-甲基腺苷（m6 A）阅读器。据报道，过表达YTHDF 2促进癌发生;然而，其在肝细胞癌（HCC）中的作用是难以捉摸的。在此，证明YTHDF 2上调并且可以预测HCC中的不良结果。YTHDF 2的泛素化水平降低有助于YTHDF 2的上调。此外，热休克蛋白90 β（HSP 90 β）和STIP 1同源性和含U盒蛋白1（STUB 1）在细胞质中与YTHDF 2物理相互作用。在机械上，HSP 90 β的大小中间结构域是其与STUB 1和YTHDF 2相互作用所必需的。HSP 90 β抑制STUB 1诱导的YTHDF 2降解，以提高YTHDF 2的表达，并进一步增强HCC的增殖和索拉非尼耐药性。此外，在HCC组织中，HSP 90 β和YTHDF 2表达上调，而STUB 1表达下调。HSP 90 β的表达与YTHDF 2蛋白水平呈正相关，而STUB 1的表达与YTHDF 2和HSP 90 β蛋白水平呈负相关。这些发现加深了对YTHDF 2如何调节以驱动HCC进展的理解，并为治疗HCC提供了潜在的靶点。本研究探讨了N6-甲基腺苷（m6 A）阅读器YTH结构域家族2（YTHDF 2）的遍在化。热休克蛋白90 β（HSP 90 β）通过抑制STIP 1同源性和含U-盒蛋白1（STUB 1）诱导的YTHDF 2泛素化促进肝细胞癌（HCC）的进展，这可能为HCC的治疗开辟一种新的干预策略。
YTH domain family 2 (YTHDF2) is the first identified N6‐methyladenosine (m6A) 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. This study explores the ubiquitination of the N6‐methyladenosine (m6A) reader, YTH domain family 2 (YTHDF2). Heat shock protein 90 beta (HSP90β) promotes the progression of hepatocellular carcinoma (HCC) by suppressing STIP1 homology and U‐box‐containing protein 1 (STUB1)‐induced YTHDF2 ubiquitination, which may inaugurate a novel intervention strategy for the treatment of HCC.
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