p38MAPK/MSK1 pathway mediated increase in histone H3Ser10 phosphorylation leads to poor prognosis in gastric cancer

Global level of histone post-translational modifications have demonstrated their diagnostic and prognostic utility in multiple cancers. However, comparative studies of histone marks between tumor and surgical resection margin tissues are minimal. Here, in human gastric cancer, status of several acetylation, methylation and phosphorylation marks of histone H3 and H4 were compared between paired tumor and resection margin tissues and phosphorylation of histone H3 Serine 10 (H3S10P) was found to be most consistent and significantly (p=0.0001) higher in tumor tissues. Immunohistochemical studies showed a significant correlation of H3S10P with tumor grade (p=0.0001), depth of invasion (p=0.0211), lymph node positivity (p=0.008) and also found to be a predictor of survival (p<0.01). In addition, the resection margins, both proximal and distal with the distance of < 4 cm showed higher level of H3S10P compared to > 4cm (p<0.01) helped in predicting survival and defining the true negative resection margin. Increase in the levels of immediate early (IE) genes c-jun, c-fos and also in mitogen and stress activated kinase 1 (MSK1) and phos-MSK1 in tumor tissues further corroborated with the increase of H3S10P in gastric cancer and suggested MAPK pathway mediated regulation of H3S10P. Further investigation of MAPK pathway both in tissues and cell lines (AGS and KATOIII) confirmed p38 MAPK/MSK1 mediated regulation of H3S10P in gastric cancer. Moreover, higher level of H3S10P and IE genes in transformed cell lines of different tissue origins (skin, liver, colon and breast) compared to their untransformed counterparts indicate the possibility of H3S10P as a tumor associated universal histone mark.