Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation.

Animals Cell Line, Tumor CpG Islands / genetics Cystathionine beta-Synthase / genetics DNA Methylation / genetics Epithelial Cells / metabolism Gene Deletion Humans Inflammation / genetics Intestines / pathology Metaplasia Mice, Transgenic Mutation / genetics Phenotype Proteome / metabolism Stomach Neoplasms / genetics Transcriptome / genetics

CBS CIMP Gastric cancer Inflammation

Journal

Genome biology

ISSN: 1474-760X

Titre abrégé: Genome Biol

Pays: England

ID NLM: 100960660

Informations de publication

Date de publication:
01 06 2021

Historique:

received: 28 01 2021

accepted: 06 05 2021

entrez: 2 6 2021

pubmed: 3 6 2021

medline: 21 1 2022

Statut: epublish

Résumé

CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H

Sections du résumé

BACKGROUND

RESULTS

We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H

CONCLUSIONS

Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H

Identifiants

DOI: 10.1186/s13059-021-02375-2 PMID: 34074348 PMC: PMC8170989

pubmed: 34074348

doi: 10.1186/s13059-021-02375-2

pii: 10.1186/s13059-021-02375-2

pmc: PMC8170989

doi:

Substances chimiques

Proteome 0

Cystathionine beta-Synthase EC 4.2.1.22

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

167

Subventions

Organisme : NCI NIH HHS

ID : P30 CA014236

Pays : United States

Commentaires et corrections

Type : ErratumIn

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