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. However, the underlying mechanism of UPS in regulating the proliferation of lipid-rich tumor cells is not totally clear. Here, 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. We 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.

中文翻译：

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PSMD1和PSMD2通过调节细胞脂质小滴代谢来调节HepG2细胞的增殖和凋亡。

肥胖和非酒精性脂肪性肝炎（NASH）是肝细胞癌（HCC）的众所周知的危险因素。富含脂质的环境增强了肿瘤细胞的增殖和转移能力。先前的研究表明泛素-蛋白酶体系统（UPS）对肿瘤细胞增殖的影响。但是，UPS在调节富含脂质的肿瘤细胞增殖中的潜在机制尚不完全清楚。在这里，我们确定了两个蛋白酶体26S亚基，非ATPase 1和2（PSMD1和PSMD2），它们通过调节细胞脂质代谢来调节HepG2细胞的增殖。简而言之，PSMD1和/或PSMD2的敲低减少了细胞脂质滴的形成，而脂质滴是肿瘤细胞增殖的能量和膜成分的提供者。机械上 PSMD1和PSMD2通过p38-JNK和AKT信号传导调节与从头脂质合成有关的基因的表达。此外，PSMD1和PSMD2的高表达与肝癌的不良预后显着相关。我们证明，PSMD1和PSMD2通过促进细胞脂质液滴的积累来促进HepG2细胞的增殖。这项研究为治疗富含脂质的肿瘤提供了潜在的治疗策略。