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Title: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
Authors: Padmanabhan, Nisha
Kyon, Huang Kie
Boot, Arnoud
Lim, Kevin
Srivastava, Supriya
Chen, Shuwen
Wu, Zhiyuan 
Lee, Hyung-O K
Mukundan, Vineeth T
Chan, Charlene
Chan, Yarn Kit 
Xuewen, Ong
Pitt, Jason J 
Isa, Zul Fazreen Adam
Xing, Manjie
Lee, Ming Hui 
Tan, Angie Lay Keng
Ting, Shamaine Ho Wei
Luftig, Micah A
Kappei, Dennis 
Kruger, Warren D
Bian, Jinsong
Ho, Ying Swan
Teh, Ming 
Rozen, Steve George
Tan, Patrick 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
Gastric cancer
Issue Date: 1-Jun-2021
Publisher: BMC
Citation: Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-O K, Mukundan, Vineeth T, Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J, Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A, Kappei, Dennis, Kruger, Warren D, Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, Tan, Patrick (2021-06-01). Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation. GENOME BIOLOGY 22 (1). ScholarBank@NUS Repository.
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.
ISSN: 1474760X
DOI: 10.1186/s13059-021-02375-2
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