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. 2019 Oct 15;79(20):5233-5244.
doi: 10.1158/0008-5472.CAN-19-0063. Epub 2019 Aug 13.

Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer

Tingting Yang #  1 , Chune Ren #  1 , Chao Lu #  1 , Pengyun Qiao #  1 , Xue Han  1 , Li Wang  1 , Dan Wang  2 , Shijun Lv  2 , Yonghong Sun  2 , Zhenhai Yu  3
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Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer

Tingting Yang et al. Cancer Res. .

Abstract

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 VSports手机版. 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 tumorigenesis in vitro and in 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. SIGNIFICANCE: These findings identify heat shock transcription factor 1 as a new substrate for PIM2 kinase and establish its role in breast tumor progression. .

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