Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice

Martin, Kelly A.; Hum, Nicholas R.; Sebastian, Aimy; He, Wei; Siddiqui, Salma; Ghosh, Paramita M.; Pan, Chong Xian; White, Ralph de Vere; Loots, Gabriela G.

doi:10.3390/ijms20204983

Cited by 12 publications

(6 citation statements)

References 25 publications

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“…Methionine adenosyltransferase 1 A (MAT1A) was a robustly downregulated pharmacogene in our data and across other studies 30,33,34,45 . Overexpression of this gene in bladder cancer tumor xenografts has been shown to confer tolerance to gemcitabine 67 suggesting that NAFLD patients could have increased liver toxicity when treated with gemcitabine due to a decreased abundance of MAT1A. Aldehyde oxidase 1 (AOX1) was another consistently downregulated pharmacogene in our data and across the other studies 26,[32][33][34] .…”

Section: Discussionsupporting

confidence: 65%

Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

et al. 2023

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Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aims to determine if patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.

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Section: Discussionsupporting

confidence: 65%

Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

et al. 2023

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“…Methionine adenosyltransferase 1a (MAT1A) is an enzyme that has a vital role in the methylation cycle by regulating S-adenosylmethionine [42]. MAT1A, which can enhance cell survival under chemotherapy, has been associated with drug resistance in bladder cancer PDX mice [43]. Torres et al found that dysregulated MAT1A gene expression resulted in a specific pattern of promoter methylation and histone acetylation [44].…”

Section: Discussionmentioning

confidence: 99%

A Novel Seventeen-Gene Metabolic Signature for Predicting Prognosis in Colon Cancer

Luo

Shan

Liu

et al. 2020

BioMed Research International

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A metabolic disorder is considered one of the hallmarks of cancer. Multiple differentially expressed metabolic genes have been identified in colon cancer (CC), and their biological functions and prognostic values have been well explored. The purpose of the present study was to establish a metabolic signature to optimize the prognostic prediction in CC. The related data were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) database, and Gene Expression Omnibus (GEO) combined with GSE39582 set, GSE17538 set, GSE33113 set, and GSE37892 set. The differentially expressed metabolic genes were selected for univariate Cox regression and lasso Cox regression analysis using TCGA and GTEx datasets. Finally, a seventeen-gene metabolic signature was developed to divide patients into a high-risk group and a low-risk group. Patients in the high-risk group presented poorer prognosis compared to the low-risk group in both TCGA and GEO datasets. Moreover, gene set enrichment analyses demonstrated multiple significantly enriched metabolism-related pathways. To sum up, our study described a novel seventeen-gene metabolic signature for prognostic prediction of colon cancer.

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“…Methionine adenosyltransferase 1A (MAT1A) was a robustly downregulated pharmacogene in our data and across other studies. 25,28,29,40 Overexpression of this gene in bladder cancer tumor xenografts has been shown to confer tolerance to gemcitabine 56 suggesting that NAFLD patients could have increased liver toxicity when treated with gemcitabine due to a decreased abundance of MAT1A. Aldehyde oxidase 1 (AOX1) was another consistently downregulated pharmacogene in our data and across the other studies.…”

Section: Discussionmentioning

confidence: 62%

Clinically Important Alterations in Pharmacogene Expression in Histologically Severe Nonalcoholic Fatty Liver Disease

Powell

Liang

Ipe

et al. 2022

Preprint

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Background Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aimed to determine if patients with histologically severe NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the spectrum of NAFLD severity. Methods We utilized hepatic RNA-seq from 93 patients with histologically staged NAFLD to test the relationship between pharmacogene expression and histological NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We then validated our results by meta-analysis of 16 studies, including ours. Results We identified 37 pharmacogene-NAFLD severity associations that were statistically significant after Bonferroni correction. Among all of the significant associations were 4 CYP enzymes (CYP2C19, CYP1B1, CYP2C8, CYP27B1), 3 phase II metabolic enzymes (GSTP1, GSTT1, GSTZ1), 6 ABC transporters (ABCB1, ABCB4, ABCB8, ABCC1, ABCC3, ABCC4), and 7 SLC transporters (SLC22A12, SLC16A1, SLCO3A1, SLC28A3, SLC2A4, SLC22A17, SLC6A6). We chose to validate CYP2C19 due to its actionability in clopidogrel prescribing and found that, compared to controls, it is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis in our meta-analysis. In the regression analyses, CYP2C19 transcript abundance decreases to 69% with every 1 unit increase in fibrosis stage; reducing CYP2C19 mRNA expression levels by 77% in individuals with stage 4 fibrosis as compared to stage 0. With every 1 unit increase in NAS, CYP2C19 transcript abundance decreases to 83%; reducing CYP2C19 mRNA expression levels by 73% in individuals with a NAS of 7 as compared to 0. Hepatic CYP2C19 transcript abundance is 63% lower in NASH compared to those without. Conclusions Our data demonstrate that mRNA expression levels of several pharmacogenes are altered in livers of patients with NAFLD. Of these, the marked down-regulation of CYP2C19 presents a clear opportunity to further develop individualized treatment modifications for drugs that are sensitive substrates of the CYP2C19 enzyme (e.g., clopidogrel).

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Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice

Cited by 12 publications

References 25 publications

Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

A Novel Seventeen-Gene Metabolic Signature for Predicting Prognosis in Colon Cancer

Clinically Important Alterations in Pharmacogene Expression in Histologically Severe Nonalcoholic Fatty Liver Disease

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