MELK is Upregulated in Advanced Clear Cell Renal Cell Carcinoma and Promotes Disease Progression by Phosphorylating PRAS40

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. However, stage IV ccRCC is generally incurable and its molecular mechanism has not yet been fully clarified. In this study, in order to screen differentially expressed genes (DEGs) between stage IV and stage I ccRCC specimens, we initially analyzed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE73731). We found that maternal and embryonic leucine zipper kinase (MELK) is upregulated in stage IV ccRCC samples and that upregulation of MELK is significantly correlated with advanced disease status. Furthermore, both loss and gain-of-function assays strengthen the evidence that MELK enforces the malignant phenotype of ccRCC cells through over-activating the mammalian target of rapamycin complex 1 (mTORC1) pathway. Mechanistically, we verified that the oncogenic effect of MELK occurs through phosphorylating PRAS40, an inhibitory subunit of mTORC1, and through disrupting the interaction between PRAS40 and raptor. In summary, these results elucidate the important role of MELK in the progression of ccRCC and indicate that MELK may be a novel regulator of ccRCC progression by over-activating the mTORC1.