Targeting the radiation-induced TR4 nuclear receptor-mediated QKI/circZEB1/miR-141-3p/ZEB1 signaling increases prostate cancer radiosensitivity

• Published in: Cancer letters 2020-12, Vol.495, p.100-111
• Main Authors: Chen, Dong, Chou, Fu-Ju, Chen, Yuhchyau, Tian, Hao, Wang, Yaqin, You, Bosen, Niu, Yuanjie, Huang, Chi-Ping, Yeh, Shuyuan, Xing, Nianzeng, Chang, Chawnshang
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Binding sites; Cancer therapies; Cell Line, Tumor; circZEB1; Deoxyribonucleic acid; DNA; Gene expression; Humans; Male; Metformin; Metformin - administration & dosage; Metformin - pharmacology; Mice; MicroRNAs - genetics; Mutagenesis; Neoplasm Transplantation; PC-3 Cells; Physiology; Plasmids; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - therapy; Proteins; QKI; Radiation; Radiation therapy; Radiation Tolerance - drug effects; Radiosensitivity; Receptors, Steroid - antagonists & inhibitors; Receptors, Steroid - metabolism; Receptors, Thyroid Hormone - antagonists & inhibitors; Receptors, Thyroid Hormone - metabolism; Ribonucleic acid; RNA; RNA, Circular - genetics; RNA-binding protein; RNA-Binding Proteins - genetics; Signal transduction; Signal Transduction - radiation effects; TR4; Transcription; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Zinc Finger E-box-Binding Homeobox 1 - genetics
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.07.040

Early studies indicated that the testicular nuclear receptor 4 (TR4) might play key roles in altering prostate cancer (PCa) progression; however, its ability to alter PCa radiosensitivity remains unclear. Here, we found that suppressing TR4 expression promoted radiosensitivity and better suppressed PCa by modulating the protein quaking (QKI)/circZEB1/miR-141-3p/ZEB1 signaling pathway. Mechanism dissection studies revealed that TR4 could transcriptionally increase the RNA-binding protein QKI to increase circZEB1 levels, which then sponges the miR-141-3p to increase the expression of its host gene ZEB1. Preclinical studies with an in vivo mouse model further proved that combining radiation therapy (RT) with metformin promoted radiosensitivity to suppress PCa progression. Together, these results suggest that TR4 may play key roles in altering PCa radiosensitivity and show that targeting this newly identified TR4-mediated QKI/circZEB1/miR-141-3p/ZEB1 signaling pathway may help in the development of a novel RT to better suppress the progression of PCa. We believe this manuscript represents a comprehensive study that should interest a broad area of readers as follows:•The prostate cancer field, when targeting TR4, can enhance the radiosensitivity.•The radiation field, that found a new possible pathway can enchance the radiosensitivity.•CircRNAs can also play an important role in prostate cancer radiosensitivity.