2. Academic Validation
  3. A novel lncRNA FLJ promotes castration resistance in prostate cancer through AR mediated autophagy

A novel lncRNA FLJ promotes castration resistance in prostate cancer through AR mediated autophagy

  • J Transl Med. 2025 Mar 3;23(1):255. doi: 10.1186/s12967-025-06294-9.
Yingying Wu # 1 2,  Shaojie Cheng # 3,  Ting Zhang 2,  Leilei Wang 2,  Ting Li 2,  Yongbo Zheng 4,  Guo Yang 4,  Xiaohou Wu 4,  Chunli Luo 2,  Tingmei Chen 2,  Liping Ou 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Chongqing University Fuling Hospital, Chongqing, China.
  • 2 Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, No.1, Yi-Xue-Yuan Road, Yu-Zhong District, Chongqing, 400016, China.
  • 3 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 4 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, No.1, Yi-Xue-Yuan Road, Yu-Zhong District, Chongqing, 400016, China. ouliping963@cqmu.edu.cn.
  • # Contributed equally.
PMID: 40033417 DOI: 10.1186/s12967-025-06294-9
Abstract

Background: Progression to castration resistance is the leading cause of death in prostate Cancer patients. Long non-coding RNAs (lncRNAs) have recently become a focal point in the regulation of Cancer development. However, few lncRNAs associated with castration-resistant prostate Cancer (CRPC) have been reported.

Methods: Firstly, we explore the CRPC associated lncRNAs by RNA Sequencing and validated using quantitative polymerase chain reaction (qRT-PCR) and RNA fluorescence in situ hybridization (RNA-FISH). The clinical significance of FLJ was evaluated in a collected Cancer cohort. Functional loss assays were performed to assess the effects of FLJ on CRPC cells both in vitro and in vivo. The regulatory mechanism of FLJ was investigated using immunohistochemistry (IHC), qRT-PCR, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays.

Results: FLJ is highly expressed in CRPC and is associated with higher stages and Gleason scores in prostate Cancer. FLJ is strongly positively correlated with Androgen Receptor (AR), which acts as a transcription factor and directly binds to the FLJ promoter region to enhance its transcription. Knockdown of FLJ inhibits CRPC cell proliferation and increases sensitivity to castration and enzalutamide (ENZA) in vitro. Mechanistically, FLJ promotes castration resistance in prostate Cancer cells by inhibiting AR nuclear import and cytoplasmic protein degradation, thereby activating the androgen-independent AR signaling pathway. Importantly, in vivo experiments showed that FLJ knockdown inhibited tumor growth and enhanced the therapeutic effect of ENZA.

Conclusions: This study identifies a novel regulatory mechanism by which lncRNA FLJ promotes CRPC progression. Sustained AR activation in CRPC acts as a transcription factor to upregulate FLJ expression. FLJ circumvents the traditional androgen-dependent survival mechanism by inhibiting AR nuclear entry and cytoplasmic protein degradation, thereby activating the AR signaling pathway. Targeting the FLJ-AR signaling axis may represent a novel therapeutic strategy for patients with castration-resistant prostate Cancer.

Keywords

Androgen receptor (AR); Autophagy; Castration resistance; Castration resistance prostate cancer (CRPC); lncRNA FLJ.

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