2. Academic Validation
  3. Histone methyltransferase KMT2D targets the SPOP-G3BP1 axis to enhance AR stability and drive castration-resistant prostate cancer progression

Histone methyltransferase KMT2D targets the SPOP-G3BP1 axis to enhance AR stability and drive castration-resistant prostate cancer progression

  • Mol Biomed. 2025 Nov 17;6(1):112. doi: 10.1186/s43556-025-00354-8.
Haoran Wen 1 2,  Maierhaba Maheremu 1,  Kaidi Zhang 1 2,  Liuru Bao 1,  Mayao Luo 1 2 3,  Yifan Zhang 1 3,  Yuanpeng Liao 1 2,  Manli Zhou 1 2,  Chenwei Wu 1,  Shidong Lv 4 5,  Xiaofu Qiu 6,  Qiang Wei 7 8 9
Affiliations

Affiliations

  • 1 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
  • 2 Department of Urology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, 341000, China.
  • 3 Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Southern Medical University, Guangzhou, Guangdong, 510080, China.
  • 4 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. [email protected].
  • 5 Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Southern Medical University, Guangzhou, Guangdong, 510080, China. [email protected].
  • 6 The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, China. [email protected].
  • 7 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. [email protected].
  • 8 Department of Urology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, 341000, China. [email protected].
  • 9 Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Southern Medical University, Guangzhou, Guangdong, 510080, China. [email protected].
PMID: 41247636 DOI: 10.1186/s43556-025-00354-8
Abstract

Castration-resistant prostate Cancer (CRPC) poses a significant clinical challenge, characterized by limited therapeutic options and unfavorable prognosis, particularly among elderly men. Reactivation of Androgen Receptor (AR) signaling remains the principal driver of CRPC cell survival and tumor progression even under castrated levels of serum androgen. Lysine methyltransferase 2D (KMT2D) has been established as a key oncogenic driver in prostate Cancer, promoting tumor progression via multiple pathways. However, its functional interaction with the AR signaling axis in the context of CRPC remains incompletely understood. In this study, we demonstrate that KMT2D substantially upregulates AR protein levels, thereby reactivating AR signaling under castration conditions. Mechanistically, KMT2D employs its Histone Methyltransferase function to transcriptionally enhance the expression of G3BP stress granule assembly factor 1 (G3BP1). Upregulated G3BP1 subsequently suppresses the activity of the E3 ubiquitin Ligase Speckle Type BTB/POZ protein (SPOP), leading to diminished AR ubiquitination and impaired proteasomal degradation. Furthermore, we explored a novel combination therapy involving the Histone Methyltransferase Inhibitor MI-503 and enzalutamide in AR-positive and AR splice variant-positive cell lines. Our results confirmed the synergistic therapeutic effects of this combination, which can continue to inhibit the AR signaling pathway during the CRPC stage, thereby delaying disease progression. Taken together, our findings elucidate a critical KMT2D/G3BP1/SPOP/AR regulatory axis in prostate Cancer progression and propose that targeted inhibition of histone methylation in combination with anti-androgen therapy represents a promising strategy for the management of advanced prostate Cancer.

Keywords

Androgen receptor; Castration-resistant; Methylation; Signaling; Ubiquitination.

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