HOMER3 orchestrates SRC-YAP1 activity that promotes tumor cell growth and antagonizes anti-tumor immunotherapy in prostate cancer.

(Yes-associated protein 1) YAP1 is frequently activated in human prostate cancers (PCa), but the underlying regulatory mechanism remains elusive. Here, we identified a novel scaffold protein HOMER3 in PCa, that can promote YAP1 activity by disrupting LATS-YAP1 phosphorylation. Mechanistically, HOMER3 overexpression in PCa facilitates the SRC kinase to phosphorylate YAP1 accompanied by counteracting LATS1-mediated YAP1 inhibition, thereby maintaining high YAP1 nuclear localization and transcriptional activity. Accordingly, HOMER3 gain-of-function in PCa cells phenocopies the effect of YAP1 activation, including cell hyperproliferation in vitro and rapid tumor growth in vivo. Additionally, transcriptome analysis revealed that CD274 is consistently upregulated in HOMER3 overexpressing PCa cells and patients, which eventually contributed to an immunosuppressive phenotype. More importantly, blocking SRC kinase-mediated YAP1 activation improved the immunotherapy-insensitive phenotypes in PCa caused by HOMER3 overexpression. Taken together, our findings define a novel kinase-substrate interactive platform for HOMER3 to orchestrate YAP1 activity in PCa. Targeting SRC-YAP1 oncogenic axis provides new insights into the therapeutic potential for PCa patients carried HOMER3 overexpression.