Ning Z, Guo X, Liu X, Lu C, Wang A, Wang X, Wang W, Chen H, Qin W, Liu X, Zhou L, Ma C, Du J, Lin Z, Luo H, Otkur W, Qi H, Chen D, Xia T, Liu J, Tan G, Xu G, Piao HL

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?) through K48-linked deubiquitination, and in ...

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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?, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPAR?, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPAR?-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Date: Dec. 21, 2021

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