Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas

Elshaer, Mohamed; El-Manawy, Ahmed Islam; Hammad, Ahmed; Namani, Akhileshwar; Wang, Xiu Jun; Tang, Xiuwen

doi:10.18632/aging.103068

Cited by 10 publications

(8 citation statements)

References 60 publications

(63 reference statements)

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“…In order to investigate the effect of KEAP1 methylation on NRF2 modulation, we correlated each KEAP1 CpGs methylation level with the expression level of NRF2 and some of its target genes that are involved in oxidative stress, oxidation-reduction processes, and the cellular response to oxidative stress: GPX2 — Glutathione Peroxidase 2, GCLC — Glutamate-Cysteine Ligase Catalytic Subunit, TXNRD1 — Thioredoxin Reductase 1, AKR1C1 — aldo-ketoreductase family 1, PGD — Phosphogluconate Dehydrogenase, SRXN1 — Sulfiredoxin 1 , and ABCC2—ATP Binding Cassette Subfamily C Member 2 [ 26 , 27 ]. An inverse, strong correlation between KEAP1 methylation and mRNA expression levels of NRF2 and its targets was observed in both the LUAD and LUSC cohorts.…”

Section: Resultsmentioning

confidence: 99%

“…In support of this idea, our group recently observed that an evaluation of each CpG methylation status at the promoter region of KEAP1 by pyrosequencing provides more information with a possible translational utility than the conventional semi-quantitative approach used until now [ 25 ]. Secondly, only some CpGs located at the promoter region and not all CpGs of KEAP1 that could exert a strong regulatory effect on its transcription and protein levels have been yet investigated [ 26 ]. As for the intragenic CpGs island of many cancer-related genes, the function of CpGs located in the gene body of KEAP1 has been poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

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Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas

et al. 2020

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Background: The KEAP1/NRF2 (Kelch-like ECH-associated protein 1/nuclear factor erythroid 2–related factor 2) pathway modulates detoxification processes and participates in the resistance of solid tumors to therapy. Scientific evidence about the presence of genetic and epigenetic abnormalities of the KEAP1 gene was firstly reported in non-small-cell lung cancer (NSCLC) and then described in other tumors. At present, the prognostic role of aberrant methylation at cytosine-guanine dinucleotide (CpG) sites of the KEAP1 gene promoter is debated in NSCLC, and its correlation with transcriptional changes and protein levels remains to be defined in large sample cohorts. Methods: We evaluated and compared multiple KEAP1 omics data (methylation, transcript, and protein expression levels) from The Cancer Genome Atlas (TCGA) to explore the role of CpGs located in different portions of KEAP1 and the correlation between methylation, transcription, and protein levels. Data from two subsets of lung adenocarcinoma (LUAD, n = 617) and lung squamous cell carcinoma (LUSC, n = 571) cohorts of NSCLC patients with different disease stages were evaluated. Results: We found that the methylation levels of many KEAP1 CpGs at various promoter and intragenic locations showed a significant inverse correlation with the transcript levels. Interestingly, these results were limited to the KRAS wild-type LUSC and LUAD cohorts, whereas in LUAD the effect of the epigenetic silencing of KEAP1 on its transcription was also observed in the EGFR mutated subpopulation. Conclusions: These results support the idea that the prognostic role of KEAP1 CpG sites warrants more in-depth investigation and that the impact of their changes in methylation levels may differ among specific NSCLC histologies and molecular backgrounds. Moreover, the observed impact of epigenetic silencing on KEAP1 expression in specific KRAS and EGFR settings may suggest a potential role of KEAP1 methylation as a predictive marker for NSCLC patients for whom anti-EGFR treatments are considered.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas

et al. 2020

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“…Log rank test P<0.05 was used as the cutoff for signi cance. The method of analysis has been discussed in a previous study (5).…”

Section: Survival Analysismentioning

confidence: 99%

“…In previous studies, we identi ed gene signatures that are regulated by the KEAP1-NRF2 pathway in lung adenocarcinoma (LUAD) and head and neck squamous cancer (HNSC) (4)(5)(6). In the current study, we used the genomics, and transcriptomics data of the ESCA cohort from TCGA to identify a gene signature regulated by the KEAP1-NRF2 pathway in ESCA.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Epithelial-mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma

Elshaer

Hammad

Wang

et al. 2020

Preprint

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BackgroundKEAP1-NRF2 pathway alterations were identified in many cancers including, esophageal cancer (ESCA). Identifying biomarkers that are associated with mutations in this pathway will aid in defining this cancer subset; and hence in supporting precision and personalized medicine. MethodsIn this study, 182 tumor samples from the Cancer Genome Atlas (TCGA)-ESCA RNA-Seq V2 level 3 data were segregated into two groups KEAP1-NRF2-mutated (22) and wild-type (160).The two groups were subjected to differential gene expression analysis and we performed Gene Set Enrichment Analysis (GSEA). Then, the enriched gene set was integrated with the differentially expressed genes (DEGs) to identify a gene signature regulated by the KEAP1-NRF2 pathway in ESCA. Furthermore, we validated the gene signature using mRNA expression data of ESCA cell lines provided by the Cancer Cell Line Encyclopedia (CCLE). The identified signature was tested in 3 independent ESCA datasets to assess its prognostic value.ResultsWe identified 11 epithelial-mesenchymal transition (EMT) genes regulated by the KEAP1-NRF2 pathway in ESCA patients. Five of the 11 genes showed significant over-expression in KEAP1-NRF2-mutated ESCA cell lines. In addition, over-expression of these five genes was significantly associated with poor survival in 3 independent ESCA datasets, including the TCGA-ESCA dataset.ConclusionAltogether, we identified a novel EMT 5-gene signature regulated by the KEAP1-NRF2 axis and this signature is strongly associated with metastasis and drug resistance in ESCA. These 5-genes are potential biomarkers and therapeutic targets for ESCA patients in whom the KEAP1-NRF2 pathway is altered.

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“…Consistent with their wide-ranging roles, some of the KLHL or KBTBD proteins are associated with somatic diseases or linked to hereditary disease [ 6 , 7 ]. Downregulation of KEAP1 ( KLHL19 ), the most well-studied KLHL family gene, is implicated in many types of cancer [ 6 , 8 ], and cancer-associated mutation of other KLHL family genes has been described [ 5 ]. Among the other diseases in which KLHL family proteins are implicated are myopathies [ 9 , 10 ], diabetes [ 11 ], pseudohypoaldosteronism (a mineral transport disorder) [ 12 ], and cardiac dysfunction [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

Ehrlich

Baribault

Ehrlich

2020

IJMS

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KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies of epigenetic factors that affect transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in super-enhancers (particularly strong, tissue-specific clusters of enhancers). The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence for an intragenic enhancer in one gene upregulating expression of its neighboring gene, specifically for KLHL40/HHATL and KLHL38/FBXO32 gene pairs. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5′ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3′ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5′ ends of genes in studies of normal and abnormal gene regulation.

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Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas

Cited by 10 publications

References 60 publications

Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas

Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas

Identification of a Novel Epithelial-mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

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Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas

Cited by 10 publications

References 60 publications

Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas

Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas

Identification of a Novel Epithelial-mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2&nbsp;Pathway in Esophageal Carcinoma

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

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Identification of a Novel Epithelial-mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma