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

## TL;DR

This study reveals how KMT2D promotes prostate cancer progression by stabilizing the androgen receptor and suggests a new combination therapy to treat advanced prostate cancer.

## Contribution

The study identifies a novel regulatory axis involving KMT2D, G3BP1, and SPOP in castration-resistant prostate cancer and proposes a synergistic treatment strategy.

## Key findings

- KMT2D increases AR protein levels by enhancing G3BP1 expression, which inhibits SPOP activity.
- Combining MI-503 with enzalutamide synergistically inhibits AR signaling in CRPC cell lines.
- The KMT2D/G3BP1/SPOP/AR axis is critical for prostate cancer progression.

## 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.

The online version contains supplementary material available at 10.1186/s43556-025-00354-8.