Nuclear protein 1 (NUPR1) is a transcriptional coregulator that has been implicated in the development of various cancer types. In addition, de novo fatty acid synthesis plays a pivotal role in hepatocellular carcinoma (HCC) development. However, little is currently known on the role of NUPR1 in hepatocellular carcinoma. In this study, bioinformatics analysis was conducted to analyze the expression level, prognosis value and enriched pathways of NUPR1 in Liver Hepatocellular Carcinoma (LIHC). We found that NUPR1 was significantly upregulated in human hepatocellular carcinoma cells compared with normal hepatocytes from LIHC patients in TCGA cohorts and our patients. Kaplan–Meier analysis and COX proportional hazard progression model showed that high expression of NUPR1 was correlated with a poor prognosis of LIHC patients. CCK-8, EdU and colony formation assays were performed to explore the effect of NUPR1 on the proliferation of HCC cells, then wound healing and transwell migration assays were performed to evaluate the effects of NUPR1 on cell migration. Furthermore, subcutaneous xenograft models were established to study tumor growth. Results showed that NUPR1 overexpression correlated with a highly proliferative and aggressive phenotype. In addition, NUPR1 knockdown significantly inhibited hepatocellular carcinoma cell proliferation and migration in vitro and hindered tumorigenesis in vivo. Mechanistically, endogenous NUPR1 could interact with sterol regulatory element binding protein 1 (SREBP1) and upregulated lipogenic gene expression of fatty acid synthase (FASN), resulting in the accumulation of lipid content. Moreover, pharmacological or genetic blockade of the NUPR1-SREBP1/FASN pathway enhanced anticancer activity in vitro and in vivo. Overall, we identified a novel function of NUPR1 in regulating hepatocellular carcinoma progression via modulation of SREBP1-mediated de novo lipogenesis. Targeting NUPR1-SREBP1/FASN pathway may be a therapeutic alternative for hepatocellular carcinoma.

核蛋白 1 (NUPR1) 是一种转录共调节因子，与各种癌症类型的发展有关。此外，从头合成脂肪酸在肝细胞癌 (HCC) 的发展中起着关键作用。然而，目前对 NUPR1 在肝细胞癌中的作用知之甚少。本研究通过生物信息学分析分析NUPR1在肝细胞癌（LIHC）中的表达水平、预后价值及富集通路。我们发现，与来自 TCGA 队列和我们患者的 LIHC 患者的正常肝细胞相比，NUPR1 在人肝细胞癌细胞中显着上调。Kaplan-Meier 分析和 COX 比例风险进展模型显示，NUPR1 的高表达与 LIHC 患者的不良预后相关。CCK-8, 进行 EdU 和集落形成测定以探索 NUPR1 对 HCC 细胞增殖的影响，然后进行伤口愈合和跨孔迁移测定以评估 NUPR1 对细胞迁移的影响。此外，建立皮下异种移植模型以研究肿瘤生长。结果表明，NUPR1 过表达与高度增殖和侵袭性表型相关。此外，NUPR1 敲低在体外显着抑制肝细胞癌细胞增殖和迁移，并在体内阻碍肿瘤发生。从机制上讲，内源性 NUPR1 可以与甾醇调节元件结合蛋白 1 (SREBP1) 相互作用，并上调脂肪酸合酶 (FASN) 的脂肪生成基因表达，从而导致脂质含量的积累。而且，NUPR1-SREBP1/FASN 通路的药理学或遗传阻断增强了体外和体内的抗癌活性。总体而言，我们确定了 NUPR1 通过调节 SREBP1 介导的从头脂肪生成来调节肝细胞癌进展的新功能。靶向 NUPR1-SREBP1/FASN 通路可能是肝细胞癌的治疗选择。