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. 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.
Highlights
Proteomic instability is one of the main reasons to cause multiple diseases in humans [1]
PIM2 physically interacts with Heat shock transcription factor 1 (HSF1) and phosphorylates it on Thr120
Immunofluorescence staining showed that PIM2 and HSF1 colocalized in the nucleus of MCF7 cells (Fig. 1F)
Summary
Proteomic instability is one of the main reasons to cause multiple diseases in humans [1]. Considering the need for healthy proteomes, the cell protection mechanism known as heat shock or proteotoxic stress response (PSR) has evolved to combat such stress, which is characterized by the induced expression of HSPs [1]. HSPs belonging to molecular chaperones regulate cellular proteostasis via protection of the misfolding, ubiquitination, and proteasomal degradation of proteins [2]. There are several transcription factors named heat shock factors (HSF) functioned to activate the proteotoxic stress-induced PSR [2]. Among these HSFs, HSF1 is the master regulator of this stressinduced transcriptional response in mammals, which plays a crucial role in preserving proteome stability [3]. Knockout HSF1 in mice abrogates HSPs induction, rendering cells vulnerable to
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