Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys 108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7 ). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A , which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7 , which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

中文翻译：

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STAT3棕榈酰化启动正反馈循环，促进小鼠肝细胞癌细胞的恶性化

转录因子 STAT3（信号转导子和转录激活子 3）的组成性激活会导致许多癌症（如肝细胞癌 (HCC)）的恶性，并与不良预后相关。Cys 的可逆棕榈酰化增加 STAT3 活性108由棕榈酰转移酶 DHHC7（编码为ZDHHC7）。在这里，我们研究了 STAT3 S-棕榈酰化在 HCC 中的后果。增加ZDHHC7对患者数据的生物信息学分析显示，HCC 病例的丰富与预后不良相关。在体外 HepG2 细胞中，DHHC7 介导的棕榈酰化增强了 STAT3 靶基因的表达，包括HIF1A，编码缺氧诱导转录因子 HIF1α。抑制 DHHC7 会降低 STAT3 的 S-棕榈酰化并降低 HIF1α 丰度。此外，细胞周期蛋白依赖性激酶 5 (CDK5) 对 HIF1α 的稳定作用使其能够促进ZDHHC7，这在 DHHC7、STAT3 和 HIF1α 之间产生了正反馈回路。扰乱该循环可减少体内 HCC 细胞的生长。此外，DHHC7、STAT3和HIF1α在人类肝癌组织中含量丰富。我们的研究确定了由 S-棕榈酰化启动的连接这些蛋白质的途径，这可能广泛适用于理解这种修饰在癌症中的作用。