CYTH4 Facilitates Renal Cell Carcinoma via Enhancing Proliferation and Likely Immune Evasion

Cytohesin-4 (CYTH4), an ARF guanine nucleotide exchange factor, remains unknown in RCC pathogenesis. We report that CYTH4 was dramatically upregulated in clear cell renal cell carcinoma (ccRCC) and following ccRCC progression. CYTH4 was strongly associated with ccRCC's immune-suppressive features and stratified ccRCC poor outcome. From CYTH4's network/NW, a multigene panel, SigCYTH4NW, was derived. In retrospective studies, (1) SigCYTH4NW effectively predicted ccRCC's inferior prognosis, was strongly associated with the well-validated poor risk ccB signature in four independent ccRCC cohorts (n = 1132), was significantly upregulated in ccB compared to ccA (favorable risk) tumors, was robustly correlated with an immune checkpoint signature (SigIC), and was predominantly expressed in tumor-associated macrophages, and (2) SigCYTH4NW effectively predicted poor prognosis and correlated with SigIC across 21 other cancer types. CYTH4 was expressed at low levels in 786-0 ccRCC cells; its stable expression promoted 786-0 cell proliferation in vitro and xenograft formation in vivo. CYTH4 bound PPP1R9B, which maintains pRb's hypophosphorylation. 786-0 CYTH4 cells displayed intensive pRb hyperphosphorylation, suggesting that CYTH4 enhances cell proliferation partially by pRb inhibition. Gene expression profiling by RNA-seq revealed a 786-0 CYTH4 network that was relevant to primary ccRCC, particularly in the aspect of immune evasion. Collectively, this study supports CYTH4's promoting ccRCC.