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

Abstract

Background 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. 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 (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. Conclusions Our 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.

Emerging roles of cystathionine β-synthase in various forms of cancer

“…In the same study, circulating tumor DNA was also analyzed for the methylation of the CBS promoter, and once again, DNA hypo methylation was detected, which was associated with worse clinical outcomes (increased recurrence rates and lower survival) [ 22 ]. According to most reports, many cancers, including colorectal, are associated with a CpG island methylator phenotype, which is characterized by aberrant, pervasive, and genome-wide DNA hypermethylation of CpG islands and subsequent global transcriptional alterations [ [57] , [58] , [59] , [60] ]. In this context, the hypomethylation of the CBS promoter appears to be atypical.…”

Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature

“…In our model, all three genes identified were associated with tumor initiation and progression (26)(27)(28). CBS encodes a homotetrameric enzyme that catalyzes the first step in the transsulfuration pathway and converses the homocysteine to cystathionine, which is associated with various stomach, liver, and ovarian cancers and influences immune evasion (29). The protein encoded by 3-hydroxyacyl-CoA dehydratase 1 (HACD1) has a protein tyrosine phosphatase (PTP) catalytic domain.…”

Characterization of the CpG island methylator phenotype subclass in papillary thyroid carcinoma

“…as an epigenetic phenotype in colorectal tumors characterized by significant hypermethylation in the promoter regions of tumor suppressor genes ( 18 ). Soon afterwards, the CIMP phenotype has been identified in many kinds of tumors, including glioma ( 20 ), renal cell carcinoma ( 21 ), gastric cancer ( 22 ), Pancreatic Cancer ( 23 ), and so forth. According to the researches, the CIMP tumor subset exhibits distinct clinicopathological, genomic/epigenomic, tumor-related immunity, and molecular features in relation to its nCIMP counterparts ( 19 , 24 , 61 ).…”

“…Occurrence of CIMP is associated with a range of genetic and environmental factors, although the molecular causes are not well-understood ( 19 ). So far, the CIMP phenotype has been identified in many kinds of tumors, including glioma ( 20 ), renal cell carcinoma ( 21 ), gastric cancer ( 22 ), Pancreatic Cancer ( 23 ), and so on. Subtypes with different CIMP patterns showed distinct clinical-pathological, genomic, and immune-related characteristics ( 24 , 25 ).…”