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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
The long noncoding RNA lncZBTB10 facilitates AR function via S-palmitoylation to promote prostate cancer progression
Shin-Chih Lin1, Yu-Sheng Cheng2, Yi-Syuan Lin1
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
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.
Insights
A novel long noncoding RNA, lncZBTB10, drives prostate cancer progression and abiraterone resistance by enhancing androgen receptor (AR) function through S-palmitoylation and nuclear condensate formation.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Androgen receptor (AR) targeted therapies are standard for prostate cancer but face inevitable drug resistance.
- Understanding novel AR activation mechanisms is key to overcoming treatment limitations.
Purpose of the Study:
- To identify novel androgen-responsive long noncoding RNAs (lncRNAs) involved in prostate cancer.
- To elucidate the mechanism of lncZBTB10 in regulating AR function and treatment resistance.
Main Methods:
- Systematic bioinformatic analysis to identify lncRNAs.
- In vitro and in vivo loss-of-function and gain-of-function studies.
- Investigation of AR S-palmitoylation and biomolecular condensate formation.
Main Results:
- lncZBTB10 (LINC02986) is overexpressed in prostate cancer, correlating with poor outcomes.
- lncZBTB10 facilitates AR function via S-palmitoylation and novel RNA-binding domain-driven nuclear condensates.
- Overexpression of lncZBTB10 promotes tumor growth and induces abiraterone resistance by increasing AR expression.
Conclusions:
- lncZBTB10 represents a novel mechanism regulating AR function in prostate cancer.
- lncZBTB10 is a potential therapeutic target for overcoming treatment resistance in prostate cancer.
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