HDAC4 modulates p27Kip1-mediated cell cycle progression in castration-resistant prostate cancer

Abstract Class IIa histone deacetylase 4 (HDAC4) primarily regulates transcription through scaffolding functions, despite its limited intrinsic deacetylase activity. Here, we identify a critical oncogenic role for HDAC4 in metastatic castration-resistant prostate cancer (mCRPC), where it is significantly overexpressed and drives disease progression by promoting proliferation, survival, and tumorigenesis. Mechanistically, HDAC4 forms a repressive complex with HDAC2 and transcription factor YY1 at the CDKN1B promoter to silence its transcription. Disruption of this complex, through genetic depletion or pharmacological inhibition, reduces HDAC2/YY1 occupancy, increases H3K27ac and RNA polymerase II enrichment, and reactivates CDKN1B expression. The resulting p27 Kip1 upregulation induces G0/G1 cell cycle arrest and apoptosis. Furthermore, HDAC4 activates context-dependent oncogenic signaling pathways, including SRC, PI3K/AKT, and ERK, through transcriptional upregulation of CUB domain-containing protein 1 (CDCP1). The selective HDAC4/5 inhibitor LMK-235 reverses this pathogenic program, reactivating CDKN1B expression and suppressing CRPC proliferation. In vivo, LMK-235 inhibits tumor growth with minimal systemic toxicity and demonstrates enhanced efficacy and cancer-cell selectivity in AR-negative CRPC models compared to the pan-HDAC inhibitor SAHA. These findings establish HDAC4 as a master epigenetic regulator in CRPC and a promising therapeutic target for this lethal disease.