SAC3 domain containing 1 intervention in energy metabolism reprogramming assists in the progression of hepatocellular carcinoma.

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.