Chip-seq of H3K79me2 binding signals in GC cells under irradation treatment
adiotherapy (RT) can prime systemic adaptive immunity against cancer cells, but an immunosuppressive tumor immune microenvironment (TIME) often impedes durable clinical outcomes. Through an in vivo metabolic transporter screening, we identify that palmitic acid (PA) uptake by cancer cells plays a vital role in radiotherapy resistance. Mechanically, we show that irradiation (IR) triggers ZDHHC19-mediated palmitoylation of PHGDH (Phosphoglycerate dehydrogenase) at Cystine 396 and 225, resulting in YAP1 activation by PHGDH increased activity. Specifically, the PHGDH metabolite 3-phosphonooxypyruvate (3-PHP) allosterically blocks LATS1 kinase activity, thereby strongly preventing phosphorylation of YAP1 leading to fully activate YAP1. Dephosphorylated YAP1 in turn escorts PHGDH into the nucleus, where PHGDH undergoes K394 acetylation by P300 and converts alpha-ketoglutarate (alpha-KG) into D-2-hydroxyglutarate (D-2HG) which inhibits the activity of KDM2B leading to a global increase of H3K79me2 and an elevation of CCL20, CD24, and CXCL1 expression. The goal of the study is to profile the H3K79me2 binding signals in wt or PHGDH R394 mutant GC cells under irradiation treatment or not, aiming to illustrate the underlying mechanism of the gene regualtion by PHGDH resulting in tumor tolerance under irradiation treatment.