BACKGROUND Hepatocellular carcinoma(HCC)is at the forefront of the global spectrum of cancer incidence and mortality,with conventional therapies like tyrosine kinase inhibitors limited by resistance.Recent studies hav...BACKGROUND Hepatocellular carcinoma(HCC)is at the forefront of the global spectrum of cancer incidence and mortality,with conventional therapies like tyrosine kinase inhibitors limited by resistance.Recent studies have highlighted the promising anticancer effects of nitidine chloride(NC)against HCC.SAC3 domain containing 1(SAC3D1)is critical for centrosome replication and spindle formation.However,research on SAC3D1 in HCC and NC remains limited.AIM To investigate the mechanisms underlying SAC3D1’s role in HCC progression and evaluated its potential as a therapeutic target of NC.METHODS RNA sequencing(RNA-seq)identified SAC3D1 expression changes in HCC cells after NC treatment.Molecular docking was further employed to validate the direct binding between NC and SAC3D1.Additionally,HCC multicenter data(The Cancer Genome Atlas_GTEx,ArrayExpress),pathway analysis,Pearson correlation analysis and SAC3D1 in vitro knockdown experiments were integrated to explore the molecular mechanisms underlying SAC3D1's involvement in HCC progression.RESULTS RNA-seq showed that NC treatment significantly downregulated SAC3D1 expression[log2(fold change)=-0.95,P<0.05],with molecular docking revealing that NC directly bound to SAC3D1 proteins(binding energy:-9.7 kcal/mol).Enrichment analysis showed that most pathways were closely related to the cell cycle.Pearson correlation analysis indicated that SAC3D1 and cell cycle genes were significantly positively correlated(correlation coefficient≥0.3,P<0.05).SAC3D1 knockdown inhibited HCC cell invasion,migration,and proliferation by arresting cells in the S and G2/M phases.Flow cytometry confirmed that after SAC3D1 knockdown,the early and total apoptosis percentage of HCC cells decreased,while the late apoptosis percentage increased.CONCLUSION As a potential target of NC,SAC3D1 may inhibit HCC progression through cell cycle regulation following its downregulation by NC.展开更多
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...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 ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-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 theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.展开更多
基金Supported by National Natural Science Foundation of China,No.82160762 and No.82460783Guangxi Medical University“Four New”Project,No.SX202403+2 种基金Innovation Project of Guangxi Graduate Education,No.JGY2023068Guangxi Higher Education Undergraduate Teaching Reform Project,No.2022JGA146China Undergraduate Innovation and Entrepreneurship Training Program,No.202310598045.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is at the forefront of the global spectrum of cancer incidence and mortality,with conventional therapies like tyrosine kinase inhibitors limited by resistance.Recent studies have highlighted the promising anticancer effects of nitidine chloride(NC)against HCC.SAC3 domain containing 1(SAC3D1)is critical for centrosome replication and spindle formation.However,research on SAC3D1 in HCC and NC remains limited.AIM To investigate the mechanisms underlying SAC3D1’s role in HCC progression and evaluated its potential as a therapeutic target of NC.METHODS RNA sequencing(RNA-seq)identified SAC3D1 expression changes in HCC cells after NC treatment.Molecular docking was further employed to validate the direct binding between NC and SAC3D1.Additionally,HCC multicenter data(The Cancer Genome Atlas_GTEx,ArrayExpress),pathway analysis,Pearson correlation analysis and SAC3D1 in vitro knockdown experiments were integrated to explore the molecular mechanisms underlying SAC3D1's involvement in HCC progression.RESULTS RNA-seq showed that NC treatment significantly downregulated SAC3D1 expression[log2(fold change)=-0.95,P<0.05],with molecular docking revealing that NC directly bound to SAC3D1 proteins(binding energy:-9.7 kcal/mol).Enrichment analysis showed that most pathways were closely related to the cell cycle.Pearson correlation analysis indicated that SAC3D1 and cell cycle genes were significantly positively correlated(correlation coefficient≥0.3,P<0.05).SAC3D1 knockdown inhibited HCC cell invasion,migration,and proliferation by arresting cells in the S and G2/M phases.Flow cytometry confirmed that after SAC3D1 knockdown,the early and total apoptosis percentage of HCC cells decreased,while the late apoptosis percentage increased.CONCLUSION As a potential target of NC,SAC3D1 may inhibit HCC progression through cell cycle regulation following its downregulation by NC.
基金Supported by the Shanghai Yangpu District Science and Technology Commission,No.YPQ202303Shanghai Municipal Health Commission Clinical Research Special Project,No.202240122Shanghai Medical Innovation Research Special Project,No.22Y11908600.
文摘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 ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-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 theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.
