The Transcription Factor ATF2 Accelerates Clear Cell Renal Cell Carcinoma Progression Through Activating the PLEKHO1/NUS1 Pathway.

Clear cell renal cell carcinoma (ccRCC) is a common malignant cancer with high mortality rate. Activating transcription factor 2 (ATF2) and pleckstrin homology domain containing O1 (PLEKHO1) were reported to participate in numerous cancers. However, their roles and the detailed mechanisms in ccRCC development remain largely unknown. RT-qPCR and western blot were used to measure the levels of PLEKHO1, ATF2, and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1). Cell proliferation, apoptosis, invasion, migration and stemness were evaluated using CCK-8 assay, flow cytometry, transwell invasion assay, wound-healing assay and sphere formation assay, respectively. Dual-luciferase reporter assay was conducted to verify the relationship between ATF2 and PLEKHO1. The interaction between PLEKHO1 and NUS1 was proved by Co-IP assay. Xenograft models were utilized to evaluate the tumorigenic capability of ccRCC cells upon PLEKHO1 knockdown. PLEKHO1, ATF2 and NUS1 expression were significantly elevated in ccRCC, and PLEKHO1 might be a prognosis biomarker for ccRCC. PLEKHO1 depletion significantly inhibited cell proliferation, invasion, migration, stemness, and induced cell apoptosis in ccRCC cells. ATF2 activated PLEKHO1 expression via transcription regulation, and PLEKHO1 overexpression could reverse the suppressive effects of ATF2 knockdown on the malignant behaviors of ccRCC cells. Moreover, PLEKHO1 directly bound to NUS1, and PLEKHO1 depletion markedly restrained ccRCC progression through targeting NUS1 in vitro and in vivo. Our findings suggested that ATF2 transcriptionally activated PLEKHO1 to promote the development of ccRCC via regulating NUS1 expression.