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

Abstract

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.

• Authors: Meng Zhang, Yin Sun, Chi-Ping Huang, Jie Luo, Li Zhang, Jialin Meng, Chaozhao Liang, Chawnshang Chang
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 10 Pg. 855 (09 20 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34545067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• 3' Untranslated Regions
• Benzamides
• Heterogeneous Nuclear Ribonucleoprotein A1
• Nitriles
• RNA, Long Noncoding
• RNA, Messenger
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Benzamides (pharmacology, therapeutic use)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Heterogeneous Nuclear Ribonucleoprotein A1 (metabolism)
• Humans
• Male
• Mice
• Models, Biological
• Mutation (genetics)
• Nitriles (pharmacology, therapeutic use)
• Phenylthiohydantoin (pharmacology, therapeutic use)
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Protein Binding (drug effects)
• Protein Biosynthesis (drug effects)
• RNA, Long Noncoding (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Androgen (metabolism)
• Transcription, Genetic (drug effects)