USP22 promotes tumorigenesis and progression by a FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma

Abstract Background: Ubiquitin-specific protease 22 (USP22) was a potential cancer stem cell (CSC) marker and could promote hepatocellular carcinoma (HCC) stemness upon tumor protein P53 (TP53) inactivation, which have been viewed as drivers of tumorigenesis. Here, we determined the role of USP22 in hepatotumorigenesis, illustrated the underlying mechanism as well as explored the therapeutic significance of USP22 in HCC. Methods: A mouse model of orthotopic HCC was established to investigate the role of USP22 during tumorigenesis. RNA-sequencing was performed to find downstream genes. Cell proliferation, counting, migration and colony formation were used to detect USP22 function in HCC cells. Immunoprecipitation and ubiquitination assay were applied to elucidate the mechanism of USP22 and FK506-binding protein 12 (FKBP12). HCC patients’ samples after liver transplantation (LT) were used to demonstrate the clinical significance. Results: Usp22 accelerated c-Myc/NRasGV12 induced HCC in mice and mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in the downstream. Besides, USP22 overexpression resulted in increased tumorigenic properties, which could be reversed by rapamycin in vitro and in vivo . USP22 activated mTORC1 by direct binding to FKBP12 and deubiquitinating it. In addition, activated mTORC1 further stabilized USP22 via inhibiting autophagic degradation in turn. Clinically, LT recipients with high USP22 expression tended to benefit from the use of sirolimus. Conclusions: USP22 promotes tumorigenesis and progression by a FKBP12/mTORC1/autophagy positive feedback loop in HCC. USP22 could be an effective biomarker for selecting eligible recipients with HCC to receive anti-mTOR-based therapies after LT.