Journal
CANCER RESEARCH
Volume 79, Issue 20, Pages 5233-5244Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-0063
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Funding
- Innovation Fund of National Natural Science Foundation of China [81602440, 81602301, 81972489]
- Shandong Province College Science and Technology Plan Project [J16LL08, J17KA254]
- projects of medical and health technology development program in Shandong province [2016WS0688, 2017WS398, 2018WS057]
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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 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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