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Padmanabhan N , Kyon HK , Boot A , Lim K , Srivastava S , Chen S , Wu Z , Lee HO , Mukundan VT , Chan C , Chan YK , Xuewen O , Pitt JJ , Isa ZFA , Xing M , Lee MH , Tan ALK , Ting SHW , Luftig MA , Kappei D , Kruger WD , Bian J , Ho YS , Teh M , Rozen SG , Tan P
Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
Genome Biol. 2021 Jun 1;22(1) :167
PMID: 34074348    PMCID: PMC8170989    URL: https://www.ncbi.nlm.nih.gov/pubmed/34074348
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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 (H(2)S), 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 H(2)S donors as a potential new therapy for CBS-silenced lesions.
1474-760x Padmanabhan, Nisha Kyon, Huang Kie Boot, Arnoud Lim, Kevin Srivastava, Supriya Chen, Shuwen Wu, Zhiyuan Lee, Hyung-Ok 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 Orcid: 0000-0002-0179-8048 Duke-NUS-KPFA/2016/0012/Khoo Postdoctoral Fellowship Award/ RL2016-080/Duke Cancer Institute (DCI) Cancer and Environment Pilot Research Award/ Duke/Duke-NUS/RECA (Pilot)/2017/0038/Duke/Duke-NUS Research Collaboration Pilot Project Award/ NMRC/STaR/0026/2015, OF-LCG18May-0023/National Medical Research Council grants/ Journal Article Genome Biol. 2021 Jun 1;22(1):167. doi: 10.1186/s13059-021-02375-2.