GSE131268
BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells
Prostate cancer (PCa) is one of the most prevalent cancers in men. PCa is clinically unpredictable; while most tumors are indolent, others exhibit lethal phenotypes. Current treatments of metastatic disease are not curative and lead to acquired resistance and relapse. Cancer stem cells (CSC) are thought to be associated with PCa relapse and represent a target against metastatic PCa. We isolated CSCs from metastatic PCa PC3 cells based on their ability to form spheres. We determined that TIP5, a factor previously implicated in aggressive PCa, is required for the formation of PCa spheres. We determined that TIP5-bromodomain (TIP5-BRD) is an epigenetic reader of H3K14ac. TIP5 genomic occupancy in PCa cells correlates with H3K14ac. We showed that a functional TIP5-BRD is required for the transition of PCa cells from a differentiated to a stem state. Mutations of TIP5-BRD or treatment with chemical probes that abrogate TIP5-BRD association with H3K14ac impair the formation of PCa spheres. Furthermore, treatment with TIP5-BRD inhibitors impairs the oncogenic transformation mediated by Pten-loss in PCa model organoids. Genome-wide occupancy analysis shows that TIP5 interacts with promoters of repressed genes in both PCa cells and metastatic tumors and with inactive enhancers that contain H3K14ac and are associated with genes implicated in developmental processes. Our findings indicate a role of TIP5 in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target TIP5 in aggressive PCa. Overall design: Examination of 4 different histone marks between 2 cell types (PC3 cells and PCa spheres (tumorspheres with cancer stem cell features). Genomewide occupancy of BAZ2A and BAZ2A bromodomain mutant in PC3 cells. Transcriptomic analysis of BAZ2A depletion in PC3 cells.