title: p38-MAPK/MSK1-mediated overexpression of histone H3 serine 10 phosphorylation defines distance-dependent prognostic value of negative resection margin in gastric cancer.
abstract: Alterations in histone modifications are now well known to result in epigenetic heterogeneity in tumor tissues; however, their prognostic value and association with resection margins still remain poorly understood and controversial. Further, histopathologically negative resection margins in several cancers have been associated with better prognosis of the disease. However, in gastric cancer, despite a high rate of R0 resection, a considerably high incidence of loco-regional recurrence is observed. We believe alterations of global histone post-translational modifications could help in identifying molecular signatures for defining the true negative surgical resection margins and also the prognosis of gastric cancer patients.
  
  
  
  The present study compares the level of H3S10ph among paired tumor and histopathologically confirmed disease-free (R0) proximal and distal surgical resection margin (PRM and DRM) tissue samples of GC patients (n = 101). Immunoblotting and immune-histochemical analysis showed a significantly (p < 0.01) higher level of H3S10ph in tumor compared to R0 surgical resection margins. Along with tumor, high H3S10ph levels in both PRM and DRM correlated with clinical parameters and poor survival. Interestingly, in the case of PRM and DRM, the association of H3S10ph with poor survival was only found in a patient group with the resection margin distance <4 cm. Further investigations revealed that the increase of H3S10ph in tumor tissues is not due to the change in cell cycle profile but rather an interphase-associated phenomenon. Moreover, an increase in ph-MSK1 and ph-p38 levels in tumor tissues and the decrease in ph-MSK1 and H3S10ph on p38 inhibition in gastric cancer cells confirmed p38-MAPK/MSK1 pathway-mediated regulation of H3S10ph in gastric cancer.
  
  
  
  Our study provides the first evidence that p38-MAPK/MSK1-regulated increase of H3S10ph in GC is predictive of a more aggressive cancer phenotype and could help in defining true negative surgical resection margin. Importantly, our data also gave a new rationale for exploration of the use of MSK1 inhibitor in gastric cancer therapy and the combination of histone post-translational modifications, H4K16ac and H4K20me3 along with H3S10ph as epigenetic prognostic markers.
authors: Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India ; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India.
authors: Shafqat Ali
authors: SA
authors: Khan
authors: Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India ; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India.
authors: Ramchandra
authors: R
authors: Amnekar
authors: Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India.
authors: Bharat
authors: B
authors: Khade
authors: Medanta - The Medicity, Gurgaon, Haryana 122001 India.
authors: Savio George
authors: SG
authors: Barreto
authors: Department of Pathology, Tata Memorial Hospital, Mumbai, MH 400012 India.
authors: Mukta
authors: M
authors: Ramadwar
authors: Department of Surgical Oncology, Gastrointestinal and Hepato-Pancreato-Biliary Service, Tata Memorial Hospital, Mumbai, MH 400012 India.
authors: Shailesh V
authors: SV
authors: Shrikhande
authors: Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India ; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India.
authors: Sanjay
authors: S
authors: Gupta
mesh_terms: D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D000072662:Margins of Excision; D010766:Phosphorylation; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D016019:Survival Analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D006657:Histones; D012694:Serine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Gastric cancer; H3S10 phosphorylation; Histone post-translational modification; Prognosis; Resection margin; p38 MAPK/MSK1 pathway