HSF1–DBC1 axis drives prostate cancer progression by activating a metastatic transcriptional program

Heat shock factor 1 (HSF1) is a key stress-protective transcription factor that acts as a guardian of proteostasis. HSF1 also plays multifaceted roles in tumor-associated processes including proliferation and metastasis. HSF1 is frequently overexpressed and activated in a wide range of cancers, including prostate cancer, and hijacked by cancer cells to promote their survival in harsh tumor microenvironments and during metastasis. However, mechanisms underlying the persistent activation of HSF1 and its coregulators in malignancies are largely unknown. Here we show that HSF1 is highly activated and required for metastatic spread and growth of metastatic castration-resistant prostate cancer (mCRPC) cells. The HSF1-driven transcriptional program and its genome occupancy in mCRPC cells were distinct from those of castration-resistant prostate cancer cells and massively reprogrammed during the metastatic progression of castration-resistant prostate cancer cells. In addition, we report DBC1 as a key coregulator of HSF1. DBC1 positively regulated HSF1-mediated transcription and genome-wide chromatin binding of HSF1. Moreover, DBC1 was required for super-enhancer formation and activation of super-enhancer-associated HSF1 target genes, including MMP11, involved in metastasis. Mechanistically, DBC1 activated and stabilized HSF1 by enhancing trimerization and DYRK2-mediated phosphorylation of HSF1 and inhibiting CHIP-mediated HSF1 ubiquitination, thereby increasing the transcriptional activity and genome-wide binding of HSF1. Importantly, DBC1 loss suppresses the metastatic growth of mCRPC cells, and HSF1–DBC1 double-high expression correlated with worse outcomes in patients with mCRPC. Our results highlight the critical role of HSF1 as a metastasis-promoting transcription factor and a novel regulatory mechanism of HSF1 activity and stability by DBC1. Thus, targeting the HSF1–DBC1 axis could be a promising therapeutic strategy for metastatic cancers.