USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma

Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPAR gamma) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPAR gamma, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPAR gamma, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPAR gamma-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition. Different deubiquitinases are associated to cancer development. Here, the authors show that PPARgamma is stabilized by USP22-mediated deubiquitination leading to lipid accumulation and promoting hepatocellular carcinoma.

Automated summary

This study reveals that USP22 stabilizes PPARgamma through deubiquitination, promoting lipid accumulation and hepatocellular carcinoma development.