Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

Journal of Experimental & Clinical Cancer Research

Caihong Lv¹  Siwen Yu²  Yue Feng²  Chen Du² 

[1] Department of Laboratory, the Fourth Affiliated Hospital of Harbin Medical University, 150001, Harbin, People’s Republic of China;Department of Urology Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, 150000, Harbin, Heilongjiang Province, People’s Republic of China;

关键词: KDM5A;    microRNA-145;    YTHDF2;    MOB3B;    m6A modification;    Prostate cancer;    Migration;    Invasion;   

DOI  :  10.1186/s13046-020-01735-3

来源: Springer

【 摘 要 】

BackgroundAccumulating evidence supports that lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers. This study was performed to elucidate the potential effects of KDM5A on prostate cancer (PCa) progression via the miR-495/YTHDF2/m6A-MOB3B axis.MethodsThe expression of KDM5A, miR-495, YTHDF2 and MOB3B was validated in human PCa tissues and cell lines. Ectopic expression and knockdown experiments were developed in PCa cells to evaluate their effects on PCa cell proliferation, migration, invasion and apoptosis. Mechanistic insights into the interaction among KDM5A, miR-495, YTHDF2 and MOB3B were obtained after dual luciferase reporter, ChIP, and PAR-CLIP assays. Me-RIP assay was used to determine m6A modification level of MOB3B mRNA in PCa cells. Mouse xenograft models of PCa cells were also established to monitor the tumor growth.ResultsKDM5A was highly expressed in human PCa tissues and cell lines. Upregulated KDM5A stimulated PCa cell proliferation, migration and invasion, but reduced cell apoptosis. Mechanistically, KDM5A, as a H3K4me3 demethylase, bound to the miR-495 promoter, which led to inhibition of its transcription and expression. As a target of miR-495, YTHDF2 could inhibit MOB3B expression by recognizing m6A modification of MOB3B mRNA and inducing mRNA degradation. Furthermore, KDM5A was found to downregulate MOB3B expression, consequently augmenting PCa cell proliferation, migration and invasion in vitro and promoting tumor growth in vivo via the miR-495/YTHDF2 axis.ConclusionIn summary, our study highlights the potential of histone demethylase KDM5A activity in enhancing PCa progression, and suggests KDM5A as a promising target for PCa treatment.

【 授权许可】

CC BY