Background and Aims:Krüppel-like factor(KLF)has a role in the occurrence,development and metabolism of can-cer.We aimed to explore the role and potential molecular mechanism of KLF13 in the growth and migration o...Background and Aims:Krüppel-like factor(KLF)has a role in the occurrence,development and metabolism of can-cer.We aimed to explore the role and potential molecular mechanism of KLF13 in the growth and migration of liver cancer cells.Methods:The expression of KLF13 in hepa-tocellular carcinoma(HCC)tissues was higher than that in normal tissues according to analysis of The Cancer Genome Atlas(TCGA)database.Lentiviral plasmids were used for overexpression and plasmid knockdown of KLF13.Real-time quantitative polymerase chain reaction(qPCR)and western blotting were used to detect mRNA and protein expression in HCC tissues and cells.Cell counting kit-8(CCK-8),colony formation,cell migration and invasion,and flow cytometry assays were used to assess the in vitro function of KLF13 in HCC cells.The effect of KLF13 on xenograft tumor growth in vivo was evaluated.The cholesterol content of HCC cells was determined by an indicator kit.A dual-luciferase reporter assay and chromatin immunoprecipitation sequencing(ChIP-seq)revealed the binding relationship between KLF13 and HMGCS1.Results:The expression of KLF13 was upregu-lated in HCC tissues and TCGA database.KLF13 knockdown inhibited the proliferation,migration and invasion of HepG2 and Huh7 cells and increased the apoptosis of Huh7 cells.The opposite effects were observed with the overexpression of KLF13 in SK-Hep1 and MHCC-97H cells.The overexpres-sion of KLF13 promoted the growth of HCC in nude mice and KLF13 transcription promoted the expression of HMGCS1 and the biosynthesis of cholesterol.KLF13 knockdown inhibited cholesterol biosynthesis mediated by HMGCS1 and inhibited the growth and metastasis of HCC cells.Conclusions:KLF13 acted as a tumor promoter in HCC by positively regulating HMGCS1-mediated cholesterol biosynthesis.展开更多
Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Th...Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.展开更多
基金the Science and Technology Program of Guizhou Province(No.[2019]1267 and[2020]4Y232).
文摘Background and Aims:Krüppel-like factor(KLF)has a role in the occurrence,development and metabolism of can-cer.We aimed to explore the role and potential molecular mechanism of KLF13 in the growth and migration of liver cancer cells.Methods:The expression of KLF13 in hepa-tocellular carcinoma(HCC)tissues was higher than that in normal tissues according to analysis of The Cancer Genome Atlas(TCGA)database.Lentiviral plasmids were used for overexpression and plasmid knockdown of KLF13.Real-time quantitative polymerase chain reaction(qPCR)and western blotting were used to detect mRNA and protein expression in HCC tissues and cells.Cell counting kit-8(CCK-8),colony formation,cell migration and invasion,and flow cytometry assays were used to assess the in vitro function of KLF13 in HCC cells.The effect of KLF13 on xenograft tumor growth in vivo was evaluated.The cholesterol content of HCC cells was determined by an indicator kit.A dual-luciferase reporter assay and chromatin immunoprecipitation sequencing(ChIP-seq)revealed the binding relationship between KLF13 and HMGCS1.Results:The expression of KLF13 was upregu-lated in HCC tissues and TCGA database.KLF13 knockdown inhibited the proliferation,migration and invasion of HepG2 and Huh7 cells and increased the apoptosis of Huh7 cells.The opposite effects were observed with the overexpression of KLF13 in SK-Hep1 and MHCC-97H cells.The overexpres-sion of KLF13 promoted the growth of HCC in nude mice and KLF13 transcription promoted the expression of HMGCS1 and the biosynthesis of cholesterol.KLF13 knockdown inhibited cholesterol biosynthesis mediated by HMGCS1 and inhibited the growth and metastasis of HCC cells.Conclusions:KLF13 acted as a tumor promoter in HCC by positively regulating HMGCS1-mediated cholesterol biosynthesis.
基金supported by the National Natural Science Foundation of China to H.Z.(Grant Nos.81770184,81970143,and 82270167)and L.Z.(Grant No.81800174)the Talent Young Program of Guangdong Province(2021B1515020017),and the Leading Talents Program from The First Affiliated Hospital of Jinan University to H.Z.
文摘Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.
