Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2025; 17(7): 107971
Published online Jul 15, 2025. doi: 10.4251/wjgo.v17.i7.107971
SAC3 domain containing 1 intervention in energy metabolism reprogramming assists in the progression of hepatocellular carcinoma
Xue-Jing Lin, Er-Jiang Tang, Bin Sun, Ai-Li Wang, Ying Chen, Lei Chen, Yi-Yang Xue, A-Jian Li, Chun-Ying Liu
Xue-Jing Lin, Er-Jiang Tang, Bin Sun, Ai-Li Wang, Ying Chen, Lei Chen, Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
Xue-Jing Lin, Chun-Ying Liu, National Center for Liver Cancer, Naval Medical University, Shanghai 201805, China
Yi-Yang Xue, Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106, United States
A-Jian Li, Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
Co-first authors: Xue-Jing Lin and Er-Jiang Tang.
Co-corresponding authors: A-Jian Li and Chun-Ying Liu.
Author contributions: Lin XJ, Li AJ, and Liu CY designed the experiments; Lin XJ and Tang EJ performed the experiments; Lin XJ, Tang EJ, and Sun B collected the data and analyzed the data; Wang AL, Chen Y, Chen L, and Xue YY performed support with experimental techniques and validated the data analysis; Li AJ and Liu CY contributed to the design, revision and study supervision; Lin XJ and Tang EJ made contributions in experimental implementation and data collection, they contributed equally to this article, they are the co-first authors of this manuscript; Li AJ and Liu CY contributed to the design, revision and funding of the research project, they contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors have read and approved the final manuscript.
Supported by the Shanghai Yangpu District Science and Technology Commission, No. YPQ202303; Shanghai Municipal Health Commission Clinical Research Special Project, No. 202240122; and Shanghai Medical Innovation Research Special Project, No. 22Y11908600.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Naval Medical University, PLA.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Chun-Ying Liu, PhD, Associate Professor, National Center for Liver Cancer, Naval Medical University, No. 366 Qianjv Road, Shanghai 201805, China.cyliu@sibcb.ac.cn
Received: April 11, 2025
Revised: May 8, 2025
Accepted: June 19, 2025
Published online: July 15, 2025
Processing time: 103 Days and 16.6 Hours
Abstract
BACKGROUND

Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma (HCC). SAC3 domain containing 1 (SAC3D1) functions in the cell cycle, and its expression is upregulated in various cancers. It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells. Based on the role of SAC3D1 in mitosis, we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism. However, it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.

AIM

To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.

METHODS

The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation, migration capabilities, as well as glycolysis and adenosine triphosphate (ATP) production rate assays. They were also employed for examining molecular markers associated with cell migration and glycolysis. The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.

RESULTS

SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients. SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo. The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production. The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway. SAC3D1 did not modulate the transcription of β-Catenin, while might inhibit its degradation. Further investigations indicated that the increase of SAC3D1 leads to more β-Catenin accumulating in the nucleus, facilitating the expression of c-Myc, one of the upstream regulatory factors of glycolysis. The iCRT3, an antagonist of β-Catenin, could counteract the increase of c-Myc induced by SAC3D1, while also downregulating the expression of glycolysis-related proteins.

CONCLUSION

This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via the β-Catenin/c-Myc signaling axis, thereby promoting the progression of HCC.

Keywords: SAC3 domain containing 1; Metabolic reprogramming; Glycolysis; Adenosine triphosphate production; β-Catenin/c-Myc axis; Hepatocellular carcinoma

Core Tip: The study revealed that the expression of SAC3 domain containing 1 (SAC3D1) was elevated in hepatocellular carcinoma and closely related to a poor prognosis. SAC3D1 facilitated the proliferation and migration of hepatocellular carcinoma cells in vitro and in vivo. The increase of SAC3D1 Leads to more β-Catenin accumulating in the nucleus, facilitating the expression of c-Myc, one of the upstream regulatory factors of glycolysis. The iCRT3, an antagonist of β-Catenin, could counteract the increase of c-Myc induced by SAC3D1, while also downregulating the expression of glycolysis-related proteins. In conclusion, SAC3D1 augmented glycolysis and adenosine triphosphate generation via β-Catenin/c-Myc axis.