Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer

Objective Cisplatinis a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatinremain obscure. Identifying genes regulating cisplatinresistance could aid clinicians in tailoring treatments, by distinguishing cisplatinsensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatinresistance. Here integrated epigenomicsis applied to identify genes associated with GC cisplatinresistance. Design 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate geneswere functionally tested by several in vitro and in vivo assays. Clinical impact of candidate geneswas also assessed in a cohort of 197 GC patients. Results Epigenomicanalysis identified bone morphogenetic protein 4( BMP4 ) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4 -expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4 -expressing GCs also did not exhibit cross resistanceto oxaliplatin. Conclusions BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatinresistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatinalternative, may represent a potential therapeutic option for BMP4 -positive GCs.