Abstract
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.
Highlights
Accumulating evidence supports that lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers
The silico analysis in the present study revealed that miR-495 could directly bind to the mRNA of YTH domain family 2 (YTHDF2), a member of the YTH domain family and the first discovered m6A reader protein, knockdown of which significantly reduces cell proliferation and migration of prostate cancer (PCa) DU-145 and PC3 cell lines [10]
Upregulated Lysine-specific demethylase 5A (KDM5A) in PCa tissues and cells was linked to an unfavorable prognosis of patients with PCa We first explored the possible role of KDM5A in the development of PCa
Summary
Accumulating evidence supports that lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers. Prostate cancer (PCa) is the most common malignancy in males and a major cause of mortality worldwide, causing approximately 1.6 million incident cases and 366,000 deaths each year [1]. Risk factors for this disease include advancing age, race, genetics, obesity, physical activity, smoking and occupation [2]. Lysine-specific demethylase 5A (KDM5A), known as a histone H3K4 demethylase [4], has recently become a promising therapeutic target for cancers due to its key. Upregulated KDM5A has been demonstrated in prostate tissues, but its downstream mechanisms remain enigmatic [8]
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