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Start Over Author "Lu, Liqing" Topic methionine adenosyltransferase
3 results on '"Lu, Liqing"'

1. Deregulated 14-3-3ζ and methionine adenosyltransferase α1 interplay promotes liver cancer tumorigenesis in mice and humans.

Author

Lu L, Zhang J, Fan W, Li Y, Wang J, Li TWH, Barbier-Torres L, Mato JM, Liu T, Seki E, Matsuda M, Tomasi ML, Bhowmick NA, Yang H, and Lu SC

Subjects
Animals, Humans, Mice, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, 14-3-3 Proteins metabolism, 14-3-3 Proteins genetics, Methionine Adenosyltransferase metabolism, Methionine Adenosyltransferase genetics, Liver Neoplasms pathology, Liver Neoplasms genetics, Liver Neoplasms metabolism, Carcinogenesis genetics, Carcinogenesis metabolism
Abstract

Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MATα1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3ζ. The MATα1/14-3-3ζ complex was critical for the expression of 14-3-3ζ. Similarly, the knockdown and small molecule inhibitor for 14-3-3ζ (BV02), and ChIP analysis demonstrated the role of 14-3-3ζ in suppressing MAT1A expression. Interaction between MATα1 and 14-3-3ζ occurs directly and is enhanced by AKT2 phosphorylation of MATα1. Blocking their interaction enabled nuclear MATα1 translocation and inhibited tumorigenesis. In contrast, overexpressing 14-3-3ζ lowered nuclear MATα1 levels and promoted tumor progression. However, tumor-promoting effects of 14-3-3ζ were eliminated when liver cancer cells expressed mutant MATα1 unable to interact with 14-3-3ζ. Taken together, the reciprocal negative regulation that MATα1 and 14-3-3ζ exert is a key mechanism in liver tumorigenesis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
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2. Reciprocal Regulation Between Forkhead Box M1/NF-κB and Methionine Adenosyltransferase 1A Drives Liver Cancer.

Author

Li Y, Lu L, Tu J, Zhang J, Xiong T, Fan W, Wang J, Li M, Chen Y, Steggerda J, Peng H, Chen Y, Li TWH, Zhou ZG, Mato JM, Seki E, Liu T, Yang H, and Lu SC

Subjects
Animals, Carcinogenesis genetics, Cell Line, Tumor, Datasets as Topic, Feedback, Physiological drug effects, Forkhead Box Protein M1 antagonists & inhibitors, Gene Expression Regulation, Neoplastic drug effects, Hepatocytes, Humans, Hydrocarbons, Fluorinated administration & dosage, Liver pathology, Liver Neoplasms drug therapy, Liver Neoplasms pathology, Male, Methionine Adenosyltransferase metabolism, Mice, Mice, Knockout, Primary Cell Culture, Promoter Regions, Genetic genetics, Pyridines administration & dosage, S-Adenosylmethionine metabolism, Sulfonamides administration & dosage, Thiophenes administration & dosage, Tumor Suppressor Proteins metabolism, Xenograft Model Antitumor Assays, Forkhead Box Protein M1 metabolism, Liver Neoplasms genetics, Methionine Adenosyltransferase genetics, NF-kappa B genetics, Tumor Suppressor Proteins genetics
Abstract

Background and Aims: Forkhead box M1 (FOXM1) and nuclear factor kappa B (NF-ĸB) are oncogenic drivers in liver cancer that positively regulate each other. We showed that methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor in the liver and inhibits NF-ĸB activity. Here, we examined the interplay between FOXM1/NF-κB and MAT1A in liver cancer., Approach and Results: We examined gene and protein expression, effects on promoter activities and binding of proteins to promoter regions, as well as effects of FOXM1 inhibitors T0901317 (T0) and forkhead domain inhibitory-6 (FDI-6) in vitro and in xenograft and syngeneic models of liver cancer. We found, in both hepatocellular carcinoma and cholangiocarcinoma, that an induction in FOXM1 and NF-κB expression is accompanied by a fall in MATα1 (protein encoded by MAT1A). The Cancer Genome Atlas data set confirmed the inverse correlation between FOXM1 and MAT1A. Interestingly, FOXM1 directly interacts with MATα1 and they negatively regulate each other. In contrast, FOXM1 positively regulates p50 and p65 expression through MATα1, given that the effect is lost in its absence. FOXM1, MATα1, and NF-κB all bind to the FOX binding sites in the FOXM1 and MAT1A promoters. However, binding of FOXM1 and NF-κB repressed MAT1A promoter activity, but activated the FOXM1 promoter. In contrast, binding of MATα1 repressed the FOXM1 promoter. MATα1 also binds and represses the NF-κB element in the presence of p65 or p50. Inhibiting FOXM1 with either T0 or FDI-6 inhibited liver cancer cell growth in vitro and in vivo. However, inhibiting FOXM1 had minimal effects in liver cancer cells that do not express MAT1A., Conclusions: We have found a crosstalk between FOXM1/NF-κB and MAT1A. Up-regulation in FOXM1 lowers MAT1A, but raises NF-κB, expression, and this is a feed-forward loop that enhances tumorigenesis., (© 2020 by the American Association for the Study of Liver Diseases.)

Published
2020
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3. Reciprocal Regulation Between Forkhead Box M1/NF-κB and Methionine Adenosyltransferase 1A Drives Liver Cancer

Author

Li, Yuan, Lu, Liqing, Tu, Jian, Zhang, Jing, Xiong, Ting, Fan, Wei, Wang, Jiaohong, Li, Meng, Chen, Yibu, Steggerda, Justin, Peng, Hui, Chen, Yongheng, Li, Tony WH, Zhou, Zhi-Gang, Mato, José M, Seki, Ekihiro, Liu, Ting, Yang, Heping, and Lu, Shelly C

Subjects
Male, Liver Cancer, S-Adenosylmethionine, Pyridines, Carcinogenesis, Knockout, Physiological, Primary Cell Culture, Chronic Liver Disease and Cirrhosis, Clinical Sciences, Immunology, Datasets as Topic, Thiophenes, Medical Biochemistry and Metabolomics, Cell Line, Feedback, Promoter Regions, Mice, Rare Diseases, Fluorinated, Genetic, Genetics, Animals, Humans, Cancer, Sulfonamides, Neoplastic, Tumor, Gastroenterology & Hepatology, Tumor Suppressor Proteins, Liver Disease, Liver Neoplasms, Forkhead Box Protein M1, NF-kappa B, Methionine Adenosyltransferase, Xenograft Model Antitumor Assays, Hydrocarbons, Liver, Gene Expression Regulation, Hepatocytes, Digestive Diseases
Abstract

Background and aimsForkhead box M1 (FOXM1) and nuclear factor kappa B (NF-ĸB) are oncogenic drivers in liver cancer that positively regulate each other. We showed that methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor in the liver and inhibits NF-ĸB activity. Here, we examined the interplay between FOXM1/NF-κB and MAT1A in liver cancer.Approach and resultsWe examined gene and protein expression, effects on promoter activities and binding of proteins to promoter regions, as well as effects of FOXM1 inhibitors T0901317 (T0) and forkhead domain inhibitory-6 (FDI-6) in vitro and in xenograft and syngeneic models of liver cancer. We found, in both hepatocellular carcinoma and cholangiocarcinoma, that an induction in FOXM1 and NF-κB expression is accompanied by a fall in MATα1 (protein encoded by MAT1A). The Cancer Genome Atlas data set confirmed the inverse correlation between FOXM1 and MAT1A. Interestingly, FOXM1 directly interacts with MATα1 and they negatively regulate each other. In contrast, FOXM1 positively regulates p50 and p65 expression through MATα1, given that the effect is lost in its absence. FOXM1, MATα1, and NF-κB all bind to the FOX binding sites in the FOXM1 and MAT1A promoters. However, binding of FOXM1 and NF-κB repressed MAT1A promoter activity, but activated the FOXM1 promoter. In contrast, binding of MATα1 repressed the FOXM1 promoter. MATα1 also binds and represses the NF-κB element in the presence of p65 or p50. Inhibiting FOXM1 with either T0 or FDI-6 inhibited liver cancer cell growth in vitro and in vivo. However, inhibiting FOXM1 had minimal effects in liver cancer cells that do not express MAT1A.ConclusionsWe have found a crosstalk between FOXM1/NF-κB and MAT1A. Up-regulation in FOXM1 lowers MAT1A, but raises NF-κB, expression, and this is a feed-forward loop that enhances tumorigenesis.

Published
2020

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