SETD2-mediated Loss Of A Panel Of MiRNAs Determines MAPK/JNK Signaling Pathway Activation And Multidrug Resistance In Renal Cell Carcinoma

Set domain-containing 2(SETD2)is the most frequently mutated gene among all the histone methyltransferases(HMTs)in Clear cell renal cell carcinoma(cc RCC).Loss of function of SETD2 is significantly associated with poor prognosis in patients with cc RCC.A better understanding of the roles of SETD2 played in cc RCC can greatly improve the prognosis and quality of life of patients with kidney cancer.To investigate the biological pathways of SETD2 involved in cc RCC,we combined the results of microarrays and RNA-seq analysis to predict the downstream pathways of SETD2.Results indicated that SETD2 was most likely to be involved in the MAPK signaling pathway and multidrug resistance(MDR)in RCC.A panel of mi RNAs,including mi R-10 b,and MAP4K4 were picked out of relevant sequencing data and both of them were correlated with oncogenesis of cc RCC.SETD2 could directly target mi R-10 b and regulate the expression of MDR-1(P-gp)through JNK pathway,which was one of the downstream pathways of MAPK pathway.After functional experiments and drug resistance experiments in vitro and in vivo,the coordinated expression of SETD2/H3K36me3-mi RNAs-MAPKs-JNK-MDR pathway was revealed to be involved in the progression and MDR of cc RCC.