The FBXW7‐RPAP2 Axis Controls the Growth of Hepatocellular Carcinoma Cells and Determines the Fate of Liver Cell Differentiation

Abstract RNA polymerase II‐associated protein 2 (RPAP2) plays a critical role in transcriptional regulation. However, little is known about whether and how RPAP2 regulates hepatocellular carcinoma (HCC) cell growth, and how the RPAP2 stability is precisely maintained. Here it is reported that high RPAP2 levels in HCC tissues correlate with poor patient survival. RPAP2 depletion suppresses the growth and survival of HCC cells. F‐box and WD repeat domain‐containing 7 (FBXW7) targets RPAP2 for polyubiquitylation and degradation after RPAP2 being pre‐phosphorylated at Ser562 and Thr565 by p38 and GSK3, respectively. HSP90 inhibition significantly promotes RPAP2 degradation by CRL5^FBXW7 ligase, whereas USP7 deubiquitylates and stabilizes RPAP2. FBXW7 knockdown promotes HCC cell growth via RPAP2 accumulation in vitro and in vivo. In mice, the hepatic‐specific deletion of Fbxw7 leads to hepatic cystogenesis with consequential accumulation of RPAP2. Simultaneous deletion of Rpap2 completely reverses the hepatic cystogenesis, indicating a causal role of RPAP2. Taken together, this study demonstrates that the RPAP2 stability is negatively regulated by FBXW7, but positively regulated by HSP90 and USP7. The FBXW7‐RPAP2 axis regulates HCC cell growth and modulates the fate of liver cell differentiation. These findings provide proof‐of‐concept evidence that oncogenic RPAP2 could be a promising therapeutic target for HCC.