PKMYT1/FOXM1/Snail Axis Promotes Metastasis in Clear Cell Renal Cell Carcinoma by Inducing Epithelial–mesenchymal Transition

Abstract Clear cell renal cell carcinoma (ccRCC), the most prevalent subtype of renal cell carcinoma, exhibits high invasiveness and metastatic potential. Membrane‐associated tyrosine/threonine 1 (PKMYT1) is linked to poor prognosis in ccRCC; however, its role in metastasis and the underlying molecular mechanisms remain unclear. Here, we analyzed PKMYT1 expression and its correlation with clinicopathological features in ccRCC using The Cancer Genome Atlas (TCGA) dataset. Exogenously modulating PKMYT1 expression in ccRCC cells, we assessed changes in cell migration, invasion, and epithelial‐mesenchymal transition (EMT) markers, and explored the involvement of the forkhead box M1 (FoxM1)/Snail axis. A mouse metastasis model was used to evaluate the impact of PKMYT1 and its downstream targets on metastasis. TCGA data showed PKMYT1 was overexpressed in ccRCC, with high expression correlating with advanced tumor grade, metastasis, and poor survival. In vitro and in vivo assays demonstrated that PKMYT1 promoted ccRCC cell migration, invasion, and metastasis. Mechanistically, PKMYT1 directly activates Snail transcription by upregulating FoxM1, which in turn represses E‐cadherin and activates vimentin expression, thereby inducing EMT in ccRCC cells. Inhibition of the FoxM1/Snail/EMT pathway reversed PKMYT1‐induced metastasis in mice. Collectively, our findings identify the PKMYT1/FoxM1/Snail axis as a driver of ccRCC metastasis via EMT induction, highlighting PKMYT1 as a potential therapeutic target for ccRCC.