Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases Enzalutamide sensitivity to better suppress prostate cancer progression

• Published in: Cell death & disease 2021-09, Vol.12 (10), p.855-855, Article 855
• Main Authors: Zhang, Meng, Sun, Yin, Huang, Chi-Ping, Luo, Jie, Zhang, Li, Meng, Jialin, Liang, Chaozhao, Chang, Chawnshang
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/51; 3' Untranslated Regions - genetics; 38; 38/77; 42; 631/154/155; 631/67/589/466; Androgen receptors; Androgens; Animals; Antibodies; Benzamides - pharmacology; Benzamides - therapeutic use; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Gene expression; Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism; Humans; Immunology; Life Sciences; Male; Mice; Models, Biological; Mutation - genetics; Nitriles - pharmacology; Nitriles - therapeutic use; Non-coding RNA; Patients; Phenylthiohydantoin - pharmacology; Phenylthiohydantoin - therapeutic use; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Binding - drug effects; Protein Biosynthesis - drug effects; Protein expression; Proteins; Receptors, Androgen - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-binding protein; Transcription, Genetic - drug effects; Tumors; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03966-4

Long non-coding RNAs (lncRNAs) have been found to play critical roles in regulating gene expression, but their function in translational control is poorly understood. We found lnc-OPHN1-5, which lies close to the androgen receptor (AR) gene on chromosome X, increased prostate cancer (PCa) Enzalutamide (Enz) sensitivity via decreasing AR protein expression and associated activity. Mechanism dissection revealed that lnc-OPHN1-5 interacted with AR-mRNA to minimize its interaction with the RNA binding protein (RBP) hnRNPA1. Suppressing lnc-OPHN1-5 expression promoted the interaction between AR-mRNA and hnRNPA1, followed by an increase of ribosome association with AR-mRNA and translation. This effect was reversed by increasing lnc-OPHN1-5 expression. Consistently, the in vivo mice model confirmed that knocking down lnc-OPHN1-5 expression in tumors significantly increased the tumor formation rate and AR protein expression compared with the control group. Furthermore, knocking down hnRNPA1 blocked/reversed shlnc-OPHN1-5-increased AR protein expression and re-sensitized cells to Enz treatment efficacy. Evidence from Enz-resistant cell lines, patient-derived xenograft (PDX) models, clinical samples, and a human PCa study accordantly suggested that patients with low expression of lnc-OPHN1-5 likely have unfavorable prognoses and probably are less sensitive to Enz treatment. In summary, targeting this newly identified lnc-OPHN1-5/AR/hnRNPA1 complex may help develop novel therapies to increase Enz treatment sensitivity for suppressing the PCa at an advanced stage.