2. Academic Validation
  3. ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway

ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway

  • Cell Mol Life Sci. 2026 Feb 9;83(1):103. doi: 10.1007/s00018-026-06092-6.
Ping Liu 1,  Baozhen Wang 1,  Hui Liu 2,  Long Liu 2,  Feifei Sun 3,  Pinpin Sui 4,  Jing Hu 2,  Lin Gao 5 6,  Bo Han 7 8
Affiliations

Affiliations

  • 1 The Key Laboratory of Experimental Teratology, Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
  • 3 Department of Pathology, Peking University People's Hospital, Beijing, China.
  • 4 Molecular Diagnostics Center, Peking University People's Hospital, Beijing, China.
  • 5 The Key Laboratory of Experimental Teratology, Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 6 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China. [email protected].
  • 7 The Key Laboratory of Experimental Teratology, Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 8 Department of Pathology, Peking University People's Hospital, Beijing, China. [email protected].
PMID: 41656388 DOI: 10.1007/s00018-026-06092-6
Abstract

Although Androgen Receptor (AR) inhibitors such as enzalutamide are initially effective in castration resistant prostate Cancer through suppression of AR signaling pathway, acquired resistance invariably develops, presenting a significant therapeutic challenge. Understanding the mechanisms of enzalutamide resistance (ENZR) is essential for developing improved therapeutic strategies. Here, we demonstrated that ZNF711 was significantly overexpressed in ENZR, and high ZNF711 levels correlated with poor clinical outcomes. Functionally, ZNF711 promoted ENZR progression both in vitro and in vivo. Mechanistically, ZNF711 directly bound to the AR promoter, transcriptionally upregulating AR expression. ZNF711 knockdown markedly reduced AR chromatin occupancy at target loci. Additionally, ZNF711 formed a complex with BMI1 and AR, enhancing AR signaling pathway by suppressing CpG methylation at the promoter of AR and its downstream target genes (e.g., KLK3, TMPRSS2), thereby potentiating AR transcriptional activity. Notably, targeting ZNF711 with antagonistic chimeric siRNA restored enzalutamide sensitivity in vivo. Collectively, our findings establish ZNF711 as a critical regulator of ENZR that promotes resistance by dually modulating the AR signaling pathway via transcriptional activation and epigenetic demethylation. Targeting the ZNF711-AR axis represents a novel therapeutic strategy to overcome ENZR in prostate Cancer.

Keywords

AR; BMI1; Enzalutamide resistance prostate cancer; Transcriptional regulation; ZNF711.

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