The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression

• Published in: Molecular cancer 2022-05, Vol.21 (1), p.119-119, Article 119
• Main Authors: Yao, Bing, Zhu, Sha, Wei, Xiyi, Chen, Ming-Kun, Feng, Yangkun, Li, Zhimin, Xu, Xinyu, Zhang, Yuwei, Wang, Yang, Zhou, Jingwan, Tang, Ningyuan, Ji, Chengjian, Jiang, Peng, Zhao, Shan-Chao, Qin, Chao, Feng, Ninghan
• Format: Article
• Language: English
• Subjects: Binding sites; CAMK2N1; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cellulose acetate; Chromatin; circSPON2; Cloning; Development and progression; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene expression; Genetic transcription; Health aspects; Histones; Humans; Immunohistochemistry; Immunoprecipitation; Male; Malignancy; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-331-3p; Next-generation sequencing; Patients; Phosphorylation; Plasmids; PRMT5; Promoters (Genetics); Prostate - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Protein arginine methyltransferase; Protein-Arginine N-Methyltransferases - genetics; Proteins; Proteins - metabolism; Ribonucleic acid; RNA; RNA, Circular - genetics; Therapeutic applications; Therapeutic targets; Transcription; Transferases; Tumorigenesis; Wound healing
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-022-01598-6

Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies. A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues. Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5. Our findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.