DBC1 promotes metastatic castration-resistant prostate cancer by enhancing the stability and activity of HSF1 [RNA-seq]
Heat shock factor 1 (HSF1) is a key stress-protective transcription factor that is exploited by various cancers to promote cancer cell survival, therapy resistance, and metastasis. Metastatic castration-resistant prostate cancer (mCRPC) is the leading cause of cancer-related death in men worldwide, and mCRPC progression is associated with increased dependence on HSF1. However, mechanisms underlying HSF1 stabilization and persistent activation in metastatic malignancies remain unclear. Here we show that the HSF1-driven transcriptional program and its genome occupancy in mCRPC cells are distinct from those of CRPC cells. HSF1 is highly activated and required for the metastatic potential of mCRPC cells. Moreover, we report DBC1 as a critical regulator of HSF1 stability and activity in mCRPC cells. DBC1 is required for genome-wide chromatin occupancy and target gene expression of HSF1. Mechanistically, DBC1 enhances DYRK2/PKA-mediated HSF1 phosphorylation at S320/S326 and inhibits CHIP-mediated HSF1 ubiquitination, thereby stabilizing and activating HSF1. Importantly, DBC1 loss suppresses growth and metastasis of mCRPC cells, and high DBC1 expression correlates with poor outcomes in patients with mCRPC. Our results highlight the critical role of DBC1 as a key HSF1 coregulator in mCRPC progression and provide insights into regulatory mechanisms of HSF1 stability and activity in advanced and metastatic cancers. Overall design: 22RV1, SM1 (derived from spine-metastasized 22RV1 cells), and their HSF1 or DBC1 knockout counterpart cells (22RV1-H1KO, 22RV1-D1KO, SM1-H1KO, and SM1-D1KO) were used for the analysis. We performed RNA sequencing (RNA-seq) in triplicates to investigate global gene expression changes induced by HSF1 or DBC1 gene knockout.