Abstract
BackgroundCIMP (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.ResultsWe 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 (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach.ConclusionsOur results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions.
Highlights
CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors
We show that loss of cystathionine beta-synthase enzyme (CBS) activity in vitro recapitulates a subset of methylation in gastric cancer (GC) CIMP tumors, and that besides GC, epimutations at CBS are associated with CIMP in other tumor types, implying a broader role in cancer
Integrative methylome, transcriptome, and proteome analysis identify highly recurrent CBS epimutations in GC CIMP To identify conserved GC CIMP epimutations, we assembled a panel of 14 gastric cell lines based on previous literature (“Methods”) that comprised 3 gastric/MSI CIMP (NUGC3, NCC59, and IM95), 3 EBV-CIMP (SNU719, YCC10 and NCC24), 6 nonCIMP GC cell lines (SNU16, SNU484, SNU1967, SNU1750, NCC19 and MKN1), and two non-malignant gastric epithelial cell lines (GES1 and HFE145)
Summary
CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Recent pan-cancer studies comparing CIMP across multiple tumor types have revealed striking tissue-specific methylation patterns, with minimal conserved hypermethylation [2]. Molecular mechanisms driving CIMP remain obscure for most cancer types with very few exceptions. Other genes and pathways implicated in CIMP include SDHB [succinate dehydrogenase complex iron sulfur subunit B] in paraganglioma [7], KRAS [KRAS proto-oncogene, GTPase], and activating BRAF [B-Raf proto-oncogene, serine/threonine kinase] mutations in colorectal cancer [8, 9]
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