SAMHD1-induced endosomal FAK signaling promotes human renal clear cell carcinoma metastasis through activating Rac1-mediated lamellipodia protrusion.

Abstract

e16523 Background: Human sterile α motif and HD domain-containing protein 1 (SAMHD1) has deoxyribonucleoside triphosphohydrolase (dNTPase) activity that allows it to defend against human immunodeficiency virus type I (HIV-1) infections and regulate the cell cycle. Although SAMHD1 mutations have been identified in various cancer types, their role in cancer is unclear. Here, we aimed to investigate the oncogenic role of SAMHD1 in human clear cell renal cell carcinoma (ccRCC), particularly as a core molecule promoting cancer cell migration. Methods: HK-2 (#22190, a normal kidney cell line), Caki-1 (#30046), Caki-2 (#30047), SN12C (#80025), and ACHN (#21611) cells were obtained from the Korean Cell Line Bank (Seoul, Korea). SN12C and ACHN cells were transfected with siRNA targeting SAMHD1. From the Broad GDAC Firehose database ( https://gdac.broadinstitute.org/ ), we downloaded RNA-sequencing (RNA-seq) and clinical data from the pankidney cohort (KIPAN), clear cell renal cell carcinoma (KIRC, ccRCC in the present study), renal papillary cell carcinoma (KIRP, PRCC in the present study), and kidney chromophobe (KICH, chRCC in the present study) datasets. We analyzed 20 pairs of human tissues (tumor and normal specimens) from Dongsan Hospital. The results are expressed as the mean ± SD or SEM. We used a two-tailed Student’s t test for single comparisons or two-way ANOVA for multiple comparisons. Results: We found that SAMHD1 participated in endocytosis and lamellipodia formation. Mechanistically, SAMHD1 contributed to the formation of the endosomal complex by binding to cortactin. Thereafter, SAMHD1-stimulated endosomal focal adhesion kinase (FAK) signaling activated Rac1, which promoted lamellipodia formation on the plasma membrane and enhanced the motility of ccRCC cells. Finally, we observed a strong correlation between SAMHD1 expression and the activation of FAK and cortactin in tumor tissues obtained from patients with ccRCC. Conclusions: In brief, these findings reveal that SAMHD1 is an oncogene that plays a pivotal role in ccRCC cell migration through the endosomal FAK-Rac1 signaling pathway.