RIOK2
Promotes Clear Cell Renal Cell Carcinoma Progression Through Cell Cycle Regulation
Hiroyuki Shikuma, Keisuke Goto, Ayako Shimo, Tomoya Hatayama, Kazuma Yukihiro, Kyosuke Iwane, Ryoken Yamanaka, Ryo Tasaka, Yuki Kohada, Kenshiro Takemoto, Kohei Kobatake, Yohei Sekino, Hiroyuki Kitano, Akihiro Goriki, Keisuke Hieda, Osamu Kaminuma, Nobuyuki Hinata ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer and is frequently associated with poor clinical outcomes. Ribosome biogenesis, which is upregulated in many malignancies, plays a key role in tumor proliferation. Right open reading frame kinase 2 (RIOK2) is an atypical kinase essential for 40S ribosomal subunit maturation, but its role in ccRCC remains unexplored. We investigated the clinical and biological significance of RIOK2 in ccRCC. Immunohistochemical analysis of 166 ccRCC specimens revealed that high RIOK2 expression was significantly associated with advanced pathological stage, higher tumor grade, and shorter cancer‐specific and progression‐free survival. Public datasets confirmed the elevated RIOK2 mRNA expression in ccRCC, and its association with poor prognosis. Functional studies demonstrated that RIOK2 knockdown suppressed the proliferation, invasion, and migration of ccRCC cells. RNA sequencing, followed by gene set enrichment analysis, revealed that RIOK2 knockdown led to the downregulation of cell cycle‐related pathways, including E2F targets. Analyses of public datasets further highlighted suppression of the G2/M checkpoint. Flow cytometry revealed G1 cell cycle arrest accompanied by reduced CDK2 protein expression in RIOK2‐knockdown cells. Furthermore, the small‐molecule RIOK2 inhibitor, NSC139021, suppressed ccRCC cell proliferation in a dose‐dependent manner, with reduced efficiency in RIOK2‐knockdown cells. Collectively, these findings identify RIOK2 as a clinically relevant factor associated with aggressive disease behavior and cell‐cycle regulation in ccRCC.