1. Academic Validation
  2. The interplay of transcriptional coregulator NUPR1 with SREBP1 promotes hepatocellular carcinoma progression via upregulation of lipogenesis

The interplay of transcriptional coregulator NUPR1 with SREBP1 promotes hepatocellular carcinoma progression via upregulation of lipogenesis

  • Cell Death Discov. 2022 Oct 28;8(1):431. doi: 10.1038/s41420-022-01213-z.
Yongjia Wang # 1 2 Yuqin Zhang # 1 Zixuan Wang # 3 Lu Yu 1 Keli Chen 4 Yuwen Xie 1 Yang Liu 1 Weijie Liang 1 Yilin Zheng 1 Yizhi Zhan 5 Yi Ding 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong province, China.
  • 2 Department of General Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong province, China.
  • 3 The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong province, China.
  • 4 Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong province, China.
  • 5 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong province, China. yizhi2012@smu.edu.cn.
  • 6 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong province, China. dingyi197980@126.com.
  • # Contributed equally.
Abstract

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.

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