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Cellular and Molecular Biology

The long noncoding RNA lncZBTB10 facilitates AR function via S-palmitoylation to promote prostate cancer progression and abiraterone resistance

British Journal of Cancer volume 132, pages 587–598 (2025)Cite this article

Subjects

Abstract

Background

Activation of androgen receptor (AR) by androgen binding to its ligand-binding domain (LBD) has led to the development of clinical drugs that target androgen biosynthesis or the LBD of AR for the treatment of prostate cancer patients. While these drugs initially offer clinical benefits, the emergence of drug resistance is inevitable after a certain duration of treatment.

Objectives

Exploring alternative AR domains or identifying novel mechanisms for AR activation is crucial for advancing prostate cancer therapies.

Methods

A systematic bioinformatic analysis identified novel androgen-responsive long noncoding RNAs (lncRNAs) in prostate cancer, which were verified using loss-of-function and gain-of-function strategies in vitro and in vivo.

Results

lncZBTB10 or LINC02986 was overexpressed in prostate cancer specimens and correlated with poor clinical outcomes. Mechanistically, our findings elucidate the pivotal role of lncZBTB10 in facilitating AR function by inducing S-palmitoylation. Moreover, the interaction between lncZBTB10 and AR not only fosters but also orchestrates biomolecular condensates within the nucleus driven by a novel RNA-binding domain, particularly in prostate cancer cells. Notably, the overexpression of lncZBTB10 not only promotes tumor growth in vivo but also triggers abiraterone resistance in vitro by inducing AR expression.

Conclusions

These results collectively reveal a novel mechanism by which lncZBTB10 regulates AR function in prostate cancer cells.

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Fig. 1: A newly identified androgen-regulated long noncoding RNA, termed lncZBTB10, is overexpressed in prostate cancer and has a positive correlation with unfavorable clinical outcomes.
Fig. 2: Androgen-induced lncZBTB10 expression facilitates the proper function of AR through a direct interaction.
Fig. 3: lncZBTB10 enhances AR S-palmitoylation and sustains its function in prostate cancer cells by inducing ZDHHC7 and ZDHHC21 expression.
Fig. 4: lncZBTB10 maintains AR nuclear localization through its N-terminal region.
Fig. 5: The upregulation of lncZBTB10 promotes tumor growth in an orthotopic mouse model of prostate cancer by inducing AR expression through ZDHHC7 and ZDHHC21.
Fig. 6: Increased lncZBTB10 expression contributes to the development of abiraterone resistance in prostate cancer cells.
Fig. 7: A cartoon that briefly summarizes the involvement of lncZBTB10 in facilitating both tumor growth and the emergence of resistance to abiraterone in prostate cancer.

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Data availability

The data supporting this article can be found both within the article itself and in its accompanying online Supplementary Material.

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Acknowledgements

We are grateful to Ching-Chin Tsai for providing technical support for the immunohistochemical staining. We also thank the technical services provided by the “Bioimage Core Facility of the National Core Facility Program for Biotechnology, National Science and Technology Council, Taiwan” for the digital transformation and quantification of the IHC data.

Funding

Research grants from the National Science and Technology Council (NSTC 109-2636-B-006-006; NSTC 110-2636-B-006-009; NSTC 111-2636-B-006-012; NSTC 112-2636-B-006-008; and NSTC 113-2636-B-006-005) and National Health Research Institutes (NHRI-EX112-11220BI and NHRI-EX113-11220BI) in Taiwan provided support for this study.

Author information

Author notes

  1. These authors contributed equally: Shin-Chih Lin, Yu-Sheng Cheng.

Authors and Affiliations

  1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Shin-Chih Lin, Yi-Syuan Lin, Wen-Tai Chiu, Ya-Chuan Tsai & Shih-Chieh Lin

  2. Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Yu-Sheng Cheng, Hsing-Yi Chen & Tsung-Yen Lin

  3. Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, 701, Taiwan

    Thi My Hang Nguyen & Wen-Tai Chiu

  4. Medical Device Innovation Center, National Cheng Kung University, Tainan, 701, Taiwan

    Wen-Tai Chiu

  5. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Shih-Chieh Lin

  6. Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Shih-Chieh Lin

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Contributions

YSC and SCL (corresponding authors) conceived the ideas and supervised the research. SCL performed the experiments and analyzed the data. YSL prepared all the constructs used in this study. TMHN and WTC conducted the confocal image analysis. YCT and HYC performed the cell experiments. SCL, YSC, and SCL (corresponding author) jointly prepared the manuscript. SCL (corresponding author) conducted the bioinformatics analyses. SCL, YSL, and YCT assisted with the animal studies. YSC and TYL provided clinical insights for the study. SCL (corresponding author) secured the funding for this study. All the authors reviewed the manuscript and consented to its publication.

Corresponding author

Correspondence to Shih-Chieh Lin.

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The authors declare no competing interests.

Ethics approval and consent to participate

We have confirmed that all methods were performed in accordance with the relevant guidelines and regulations. Approval for all the animal studies was obtained from the Institutional Animal Care and Use Committee (IACUC: 108299) at the Laboratory Animal Center, NCKU.

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Lin, SC., Cheng, YS., Lin, YS. et al. The long noncoding RNA lncZBTB10 facilitates AR function via S-palmitoylation to promote prostate cancer progression and abiraterone resistance. Br J Cancer 132, 587–598 (2025). https://doi.org/10.1038/s41416-025-02938-1

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