Abstract
BackgroundObesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC). The lipid-rich environment enhances the proliferation and metastasis abilities of tumor cells. Previous studies showed the effect of the ubiquitin–proteasome system (UPS) on tumor cell proliferation. However, the underlying mechanism of UPS in regulating the proliferation of lipid-rich tumor cells is not totally clear.ResultsHere, we identify two proteasome 26S subunits, non-ATPase 1 and 2 (PSMD1 and PSMD2), which regulate HepG2 cells proliferation via modulating cellular lipid metabolism. Briefly, the knockdown of PSMD1 and/or PSMD2 decreases the formation of cellular lipid droplets, the provider of the energy and membrane components for tumor cell proliferation. Mechanically, PSMD1 and PSMD2 regulate the expression of genes related to de novo lipid synthesis via p38-JNK and AKT signaling. Moreover, the high expression of PSMD1 and PSMD2 is significantly correlated with poor prognosis of HCC.ConclusionWe demonstrate that PSMD1 and PSMD2 promote the proliferation of HepG2 cells via facilitating cellular lipid droplet accumulation. This study provides a potential therapeutic strategy for the treatment of lipid-rich tumors.
Highlights
Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC)
The cell proliferation capacity was detected by the MTT method, indicating that the cell proliferation process was significantly inhibited by the downregulation of proteasome 26S subunit (PSMD1) and proteasome 26S subunit (PSMD2) (p < 0.05, Fig. 1a)
The results indicated that more cells were blocked in the S-stage by PSMD1 and PSMD2 knockdown (Fig. 1b, c)
Summary
Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC). The lipid-rich environment enhances the proliferation and metastasis abilities of tumor cells. Previous studies showed the effect of the ubiquitin–proteasome system (UPS) on tumor cell proliferation. The underlying mechanism of UPS in regulating the proliferation of lipid-rich tumor cells is not totally clear. Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are usually enhanced by obesity, are well-known risk factors of HCC [2, 3]. Evidence indicates that a higher level of LDs in cancer cells is associated with higher tumor aggressiveness [14, 15]. The LD-related proteins are involved in the regulation of cellular lipid metabolism
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