Affiliations
1Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore.
2Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.
3Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
4Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore.
5Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
6Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
7Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
8Department of Molecular Genetics and Microbiology, Duke Centre for Virology, Duke University School of Medicine, Durham, NC, USA.
9Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.
10National University of Singapore (Suzhou) Research Institute, Suzhou, 215123, China.
11Department of Pathology, National University of Singapore, Singapore, 119228, Singapore.
12Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore. gmstanp@duke-nus.edu.sg.
13Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. gmstanp@duke-nus.edu.sg.
14Genome Institute of Singapore, Singapore, 138672, Singapore. gmstanp@duke-nus.edu.sg.
15SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, 169856, Singapore. gmstanp@duke-nus.edu.sg.
16Singapore Gastric Cancer Consortium, Singapore, 119074, Singapore. gmstanp@duke-nus.edu.sg.
17Department of Physiology, National University of Singapore, Singapore, 117593, Singapore. gmstanp@duke-nus.edu.sg.
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-?B 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.
Keywords: CBS; CIMP; Gastric cancer; Inflammation.
PMID: 34074348 DOI: 10.1186/s13059-021-02375-2