SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization.
SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization.
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SHF 通过破坏 STAT3 二聚化作为多形性胶质母细胞瘤的新型肿瘤抑制剂
DOI：
10.1002/advs.202200169
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发表时间：
2022-09
期刊：
影响因子：
15.1
通讯作者：
Zou, Jian
中科院分区：
文献类型：
--
作者：
Wang, Jingjing;Huang, Zixuan;Ji, Li;Chen, Cheng;Wan, Quan;Xin, Yu;Pu, Zhening;Li, Koukou;Jiao, Jiantong;Yin, Ying;Hu, Yaling;Gong, Lingli;Zhang, Rui;Yang, Xusheng;Fang, Xiangming;Wang, Mei;Zhang, Bo;Shao, Junfei;Zou, Jian
关键词：
信号转导和转录激活子3(STAT3)的持续激活是肿瘤发生和化疗耐药的关键因素，因此使其成为一个有吸引力的肿瘤治疗靶点。在这里，含有SH2结构域的适配蛋白F(SHF)被认为是多形性胶质母细胞瘤(GBM)中的一种肿瘤抑制因子，并研究了其对STAT3活性的负调控。在机械上，SHF选择性地结合和抑制乙酰化的STAT3二聚，而不影响STAT3的磷酸化或乙酰化。此外，通过阻断STAT3-DNMT1(DNA甲基转移酶1)的相互作用，SHF缓解了肿瘤抑制基因的甲基化。SH2域被证明是SHF对STAT3的操作所必需的，并且几乎完全独立地取代了STAT3上的SHF的功能。此外，从SHF的STAT3结合部位衍生的C16α肽抑制了STAT3的二聚化和STAT3/DNMT1的相互作用，在体内外对GBM细胞的生长都有显著的抑制作用。这些发现有力地证明了以SHF/STAT3相互作用为靶点是开发最佳STAT3抑制剂的有前景的策略，并为STAT3抑制剂如C16在GBM中的潜在临床疗效提供了早期证据。含有SH2结构域的适配蛋白F(SHF)在胶质母细胞瘤中被鉴定为肿瘤抑制因子，其对STAT3活性的负调节特征是破坏乙酰化的STAT3二聚化和STAT3-DNMT1相互作用，从而减轻肿瘤抑制基因的甲基化，并且针对SHF的STAT3结合部位的多肽被证明是一种抑制策略。
Sustained activation of signal transducer and activator of transcription 3 (STAT3) is a critical contributor in tumorigenesis and chemoresistance, thus making it an attractive cancer therapeutic target. Here, SH2 domain‐containing adapter protein F (SHF) is identified as a tumor suppressor in glioblastoma Multiforme (GBM) and its negative regulation of STAT3 activity is characterized. Mechanically, SHF selectively binds and inhibits acetylated STAT3 dimerization without affecting STAT3 phosphorylation or acetylation. Additionally, by blocking STAT3‐DNMT1 (DNA Methyltransferase 1) interaction, SHF relieves methylation of tumor suppressor genes. The SH2 domain is documented to be essential for SHF's actions on STAT3, and almost entirely replaces the functions of SHF on STAT3 independently. Moreover, the peptide C16 a peptide derived from the STAT3‐binding sites of SHF inhibits STAT3 dimerization and STAT3/DNMT1 interaction, and achieves remarkable growth inhibition in GBM cells in vitro and in vivo. These findings strongly identify targeting of the SHF/STAT3 interaction as a promising strategy for developing an optimal STAT3 inhibitor and provide early evidence of the potential clinical efficacy of STAT3 inhibitors such as C16 in GBM. SH2 domain‐containing adapter protein F (SHF) is identified as tumor suppressor in glioblastoma and its negative regulation of STAT3 activity is characterized by disrupting acetylated STAT3 dimerization and STAT3‐DNMT1 interaction, thereby relieving methylation of tumor suppressor genes, and a peptide targeting STAT3‐binding sites of SHF is demonstrated as a suppressive strategy.
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影响因子：
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作者：
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通讯作者：
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影响因子：
50.3
作者：
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作者：
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DOI：
10.1016/j.bbagen.2019.05.019
发表时间：
2019-09-01
影响因子：
3
作者：
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通讯作者：
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