Sperm associated antigen 4 promotes SREBP1-mediated de novo lipogenesis via interaction with lamin A/C and contributes to tumor progression in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor and its progression is associated with altered lipid metabolism in precancerous lesions, such as non-alcoholic fatty liver disease. Here, we identified sperm associated antigen 4 (SPAG4), and explored its oncogenic role in HCC progression. Database analysis and immunohistochemistry indicated increased level of SPAG4 in HCC tissues which was of prognostic value. Gain/loss-of-function experiments showed that SPAG4 exerted oncogenic roles in HCC growth both in vitro and in vivo. RNA sequencing revealed activation of a lipogenic state and SREBP1-mediated pathway following SPAG4 overexpression. Mechanistically, the N-terminal region of SPAG4 bound to lamin A/C, which increased SREBP1 expression, nuclear translocation, and transcriptional activity. Treatment with orlistat, a lipid synthesis inhibitor, reversed SPAG4-mediated oncogenic effects, and its efficacy varied with SPAG4 level. The effect of orlistat was further amplified when combined with sorafenib in tumor xenograft mouse models. Our study provides evidence that SPAG4 mediates HCC progression by affecting lipid metabolism. Administration of orlistat combined with sorafenib reverses SPAG4-mediated oncogenesis in HCC cells and ectopic xenograft tumors in mice, suggesting that this pathway represents a potential target for HCC treatment.

• Authors: Tengfei Liu, Junming Yu, Chao Ge, Fangyu Zhao, Jing Chen, Chunxiao Miao, Wenjiao Jin, Qingqing Zhou, Qin Geng, Hechun Lin, Hua Tian, Taoyang Chen, Haiyang Xie, Ying Cui, Ming Yao, Xiuying Xiao, Jinjun Li, Hong Li
• Journal: Cancer letters (Cancer Lett) Vol. 536 Pg. 215642 (06 28 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 35307486 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Carrier Proteins
• Lamin Type A
• Orlistat
• Sorafenib
• Sterol Regulatory Element Binding Protein 1

Topics

• Animals
• Humans
• Mice
• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Lamin Type A (genetics, metabolism, pharmacology)
• Lipogenesis (genetics)
• Liver Neoplasms (drug therapy, genetics, metabolism)
• Orlistat (metabolism, pharmacology)
• Sorafenib (pharmacology)
• Sterol Regulatory Element Binding Protein 1 (metabolism)