![]() ![]() We hope our findings may provide new concepts of PCa biology. ![]() We propose a novel regulatory mechanism in which YTHDF2 mediates the mRNA degradation of the tumor suppressors LHPP and NKX3–1 in m 6A-dependent way to regulate AKT phosphorylation-induced tumor progression in prostate cancer. Phosphorylated AKT was consequently confirmed as the downstream of METT元/YTHDF2/LHPP/NKX3–1 to induce tumor proliferation and migration. Overexpression of LHPP and NKX3–1 presented the consistent phenotypes and AKT phosphorylation inhibition with knock-down of YTHDF2 or METT元. Knock-down of YTHDF2 or METT元 significantly induced the expression of LHPP and NKX3–1 at both mRNA and protein level with inhibited phosphorylated AKT. YTHDF2 directly bound to the m 6A modification sites of LHPP and NKX3–1 to mediate the mRNA degradation. LHPP and NKX3–1 were identified as the direct targets of both YTHDF2 and METT元. Knocking down YTHDF2 or METT元 markedly inhibited the proliferation and migration of PCa in vivo and in vitro. The upregulated YTHDF2 and METT元 in PCa predicted a worse overall survival rate. ![]() In addition, TCGA database was also used to analyze the expression pattern of YTHDF2, METT元 and the common target LHPP in PCa, and their correlation with clinical prognosis. m 6A RNA immunoprecipitation (MeRIP) sequencing, mRNA sequencing, RIP-RT-qPCR and bioinformatics analysis were mainly used to screen and validate the direct common targets of YTHDF2 and METT元. Subcutaneous xenografts and metastatic mice models were combined with in vivo imaging system to investigate the phenotypes when knocking down YTHDF2 and METT元. Colony formation, flow cytometry and trans-well assays were performed for cell function identifications. Endogenous expression silencing of YTHDF2 and METT元 was established with lentivirus-based shRNA technique. To investigate the functions and mechanisms of YTHDF2 in PCa, in vitro, in vivo biofunctional assays and epigenetics experiments were performed. However, the function and mechanisms of m 6A especially YTHDF2 in prostate cancer (PCa) still remain elusive. As a crucial reader, YTHDF2 usually mediates the degradation of m 6A-modified mRNAs in m 6A-dependent way. Emerging evidence has supported the fact that m 6A is comprehensively involved in various diseases especially cancers. N6-methyladenosine (m 6A) is the most abundant modification in mRNA of humans. ![]()
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