Abstract

Prostate cancer (PCa) progression, particularly to castration-resistant prostate cancer (CRPC), is driven by androgen receptor (AR) reactivation and epigenetic alterations. Here, we identify lysine methyltransferase 2D (KMT2D) as a critical epigenetic oncogene in PCa. KMT2D expression is elevated in PCa and correlates with poor prognosis. Mechanistically, KMT2D facilitates AR signaling by recruiting the pioneer factor FOXA1 to AR-specific enhancers, promoting chromatin accessibility and activating AR target genes. FOXA1 mutations impair this regulation, demonstrating their functional interplay. Furthermore, KMT2D-FOXA1-AR axis modulates ketone body metabolism via transcriptional control of HMGCS2, supporting tumor growth. Pharmacological inhibition of UTX, a COMPASS complex demethylase essential for KMT2D function, disrupts H3K4me1 deposition and suppresses AR signaling and tumor proliferation. Altogether, we characterize KMT2D as a key driver of AR-dependent PCa progression and propose UTX inhibition as a promising therapeutic strategy.