Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Histone methyltransferase KMT2D promotes castration-resistant prostate cancer progression by reactivating AR through FOXA1

  • 期刊论文

  • 发表日期：

    2026年5月30日

查看全文
  • Mayao Luo,
  • Chenwei Wu,
  • Manli Zhou,
  • Rui Liu,
  • Yifan Zhang,
  • Yadong Li,
  • Yuanpeng Liao,
  • Xin Huang,
  • Chuance Du,
  • Shidong Lv,
  • Qiang Wei

摘要

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.