SKP2-mediated FBXO2 proteasomal degradation drives hepatocellular carcinoma progression via stabilizing Hsp47

Accumulating studies highlight that dysregulated E3 ubiquitin ligases are associated with the onset and advancement of cancers. Nevertheless, the impact and mechanism of most E3 ubiquitin ligases on tumorigenesis and tumor metastasis remain poorly understood. Here, we show that loss of FBXO2, an E3 ubiquitin ligase, accelerates hepatocellular carcinoma (HCC) tumor growth and metastasis to the lung through stabilizing heat shock protein 47 (Hsp47). Downregulation of FBXO2, caused by DNA-PKcs-medicated phosphorylation at serine 17 and E3 ligase SKP2-mediated ubiquitination at lysine 79 and subsequent proteasomal degradation, is observed in tumor tissues compared to their parallel non-tumor tissues resected from patients with HCC. Patients whose tumors are enriched for SKP2 or Hsp47 or express low levels of FBXO2 have poor median survival compared to those whose tumors have reversed levels of SKP2, FBXO2 and Hsp47. Together, FBXO2 acts as a tumor suppressor in HCC development. The components of the SKP2-FBXO2-Hsp47 axis provide newly prognostic and therapeutic factors for anti-HCC.