Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression
- PDF / 3,395,081 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 110 Downloads / 146 Views
(2020) 39:223
RESEARCH
Open Access
Activation of the KDM5A/miRNA-495/ YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression Chen Du1*, Caihong Lv2, Yue Feng1 and Siwen Yu1
Abstract Background: Accumulating 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. Methods: The 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, miR495, 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. Results: KDM5A 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. Conclusion: In 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. Keywords: KDM5A, microRNA-145, YTHDF2, MOB3B, m6A modification, Prostate cancer, Migration, Invasion
Background 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]. There are multiple * Correspondence: [email protected] 1 Department of Urology Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin 150000, Heilongjiang Province, People’s Republic of China Full list of author information is available at the end of the article
management options for men with PCa, such as surgery, radiation, chemotherapy, vaccines, hormonal therapeutics, and bone-targeting agents [3]. Despite the efficacy these approaches demonstrated, novel means to assess the presence of PCa, monitor its progression and predict its outcome at an early stage in a reliable manner are still required, which necessitate a better understanding of its underlying molecular processe
Data Loading...
