Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer
Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer
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PIM2 磷酸化 HSF1 可诱导 PD-L1 表达并促进乳腺癌中的肿瘤生长。
DOI：
10.1158/0008-5472.can-19-0063
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发表时间：
2019
期刊：
影响因子：
11.2
通讯作者：
Yu Zhenhai
中科院分区：
文献类型：
--
作者：
Yang Tingting;Ren Chune;Lu Chao;Qiao Pengyun;Han Xue;Wang Li;Wang Dan;Lv Shijun;Sun Yonghong;Yu Zhenhai
热休克转录因子1（HSF 1）是蛋白毒性应激反应的主要调节因子，在乳腺癌的发生中起着关键作用。然而，HSF 1蛋白稳定性的调节机制仍不清楚。在这里，我们表明，HSF 1蛋白的稳定性是由PIM 2介导的磷酸化HSF 1在Thr 120，这破坏了结合的HSF 1的E3泛素连接酶FBXW 7。此外，HSF 1 Thr 120磷酸化促进蛋白质稳态和卡铂诱导的自噬。有趣的是，HSF 1 Thr 120磷酸化诱导HSF 1与PD-L1启动子结合并增强PD-L1表达。此外，HSF 1 Thr 120磷酸化促进乳腺癌在体外和体内的肿瘤发生。乳腺癌组织中PIM 2、pThr 120-HSF 1和PD-L1的表达呈正相关。总的来说，这些研究结果确定PIM 2介导的HSF 1磷酸化在Thr 120作为一个重要的机制，调节乳腺癌的生长和潜在的治疗靶点为breastcancer.SignificanceThese研究结果确定热休克转录因子1作为一个新的底物PIM 2激酶，并建立其在乳腺肿瘤进展的作用。
Heat shock transcription factor 1 (HSF1) is the master regulator of the proteotoxic stress response, which plays a key role in breast cancer tumorigenesis. However, the mechanisms underlying regulation of HSF1 protein stability are still unclear. Here, we show that HSF1 protein stability is regulated by PIM2-mediated phosphorylation of HSF1 at Thr120, which disrupts the binding of HSF1 to the E3 ubiquitin ligase FBXW7. In addition, HSF1 Thr120 phosphorylation promoted proteostasis and carboplatin-induced autophagy. Interestingly, HSF1 Thr120 phosphorylation induced HSF1 binding to the PD-L1 promoter and enhanced PD-L1 expression. Furthermore, HSF1 Thr120 phosphorylation promoted breast cancer tumorigenesisin vitroandin vivo. PIM2, pThr120-HSF1, and PD-L1 expression positively correlated with each other in breast cancer tissues. Collectively, these findings identify PIM2-mediated HSF1 phosphorylation at Thr120 as an essential mechanism that regulates breast tumor growth and potential therapeutic target for breast cancer.SignificanceThese findings identify heat shock transcription factor 1 as a new substrate for PIM2 kinase and establish its role in breast tumor progression.