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1.
Nat Commun ; 11(1): 708, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024842

RESUMO

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.


Assuntos
Processamento Alternativo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Helicases/genética , Idoso , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes myc , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glicólise/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos SCID , Pessoa de Meia-Idade , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Regiões Promotoras Genéticas , RNA Helicases/metabolismo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
2.
Cancer Manag Res ; 11: 9203-9212, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754310

RESUMO

PURPOSE: Micheliolide (MCL) is an effector compound of the flower which has been traditionally used to treat inflammation and cancer patients in oriental medicine. MCL has killing effects on several cancer and immune cells by modulating apoptosis, cell cycle, and metabolism. However, the detail of the mechanisms of anti-cancer activity remains to be elucidated and the effect on liver cancer cells is unknown. METHODS: Cell proliferation was determined by CCK8 and clone formation assay. The xenograft liver cancer model formed by injecting Huh7 cells into NUDE mice was used to evaluate the effects of MCL on liver cancer cells in vivo. We evaluated the stemness of cells with spheroid formation assay and flow cytometry assay. The apoptosis was determined by Annexin V assay. F-actin staining and ROS were performed to detect the impairment of the F-actin cytoskeleton and mitochondria. RESULTS: Here, we first show that MCL inhibits liver cancer cells both in vivo and in vitro by triggering apoptosis which was reduced by anti-oxidant, but not cell-cycle arrest. In addition, MCL induces mitochondrial ROS and caspase-3 activation. Also, we found that the aggregation of mitochondria and the perturbation of F-actin fibers in the MCL-treated liver cancer cells coincidently occurred before the induction of apoptosis and mitochondrial ROS. CONCLUSION: These results suggest that F-actin perturbation is involved in impaired mitochondria and apoptosis. Therefore, MCL can be a potent therapeutic reagent for liver cancer, primarily targeting the actin cytoskeleton.

3.
Protein Cell ; 10(9): 668-680, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31152430

RESUMO

Human embryonic stem cells (hESCs) depend on glycolysis for energy and substrates for biosynthesis. To understand the mechanisms governing the metabolism of hESCs, we investigated the transcriptional regulation of glucose transporter 1 (GLUT1, SLC2A1), a key glycolytic gene to maintain pluripotency. By combining the genome-wide data of binding sites of the core pluripotency factors (SOX2, OCT4, NANOG, denoted SON), chromosomal interaction and histone modification in hESCs, we identified a potential enhancer of the GLUT1 gene in hESCs, denoted GLUT1 enhancer (GE) element. GE interacts with the promoter of GLUT1, and the deletion of GE significantly reduces the expression of GLUT1, glucose uptake and glycolysis of hESCs, confirming that GE is an enhancer of GLUT1 in hESCs. In addition, the mutation of SON binding motifs within GE reduced the expression of GLUT1 as well as the interaction between GE and GLUT1 promoter, indicating that the binding of SON to GE is important for its activity. Therefore, SON promotes glucose uptake and glycolysis in hESCs by inducing GLUT1 expression through directly activating the enhancer of GLUT1.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica , Transportador de Glucose Tipo 1/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Antígenos de Histocompatibilidade Menor/fisiologia , Elementos Facilitadores Genéticos/genética , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Glicólise , Células-Tronco Embrionárias Humanas/citologia , Humanos , Regiões Promotoras Genéticas/genética
4.
Sci Rep ; 7(1): 5463, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28710479

RESUMO

Inactivation of the VHL tumour suppressor gene is a highly frequent genetic event in the carcinogenesis of central nervous system-(CNS) hemangioblastomas (HBs). The patterning of the similar embryonic vasculogenesis is an increasing concern in HB-neovascularization, and the classic vascular endothelial growth factor (VEGF)-mediated angiogenesis driven by VHL loss-of-function from human endothelium have been questioned. With this regard, we identify a distinct, VHL silencing-driven mechanism in which human vascular endothelial cells by means of increasing cell proliferation and decreasing cell apoptosis, is concomitant with facilitating accumulation of Twist1 protein in vascular endothelial cells in vitro. Importantly, this molecular mechanism is also pinpointed in CNS-HBs, and associated with the process of HB-neovascularization. In contrast with recent studies of HB-neovascularization, these modified cells did not endow with the typical features of vasculogenesis, indicating that this is a common angiogenesis implementing the formation of the vascular network. Taken together, these findings suggest that vasculogenesis and angiogenesis may constitute complementary mechanisms for HB-neovascularization, and could provide a rational recognition of single anti-angiogenic intervention including targeting to the Twist1 signalling for HBs.


Assuntos
Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica , Hemangioblastoma/genética , Neovascularização Patológica/genética , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Apoptose , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/irrigação sanguínea , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Células HEK293 , Hemangioblastoma/irrigação sanguínea , Hemangioblastoma/metabolismo , Hemangioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteína 1 Relacionada a Twist/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
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