p38-MAPK/MSK1-mediated overexpression of histone H3 serine 10 phosphorylation defines distance-dependent prognostic value of negative resection margin in gastric cancer

Shafqat Ali Khan, Ramchandra Amnekar, Bharat Khade, Savio Barreto, Mukta Ramadwar, Shailesh V Shrikhande, Sanjay Gupta

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Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Article number88
Number of pages16
JournalClinical Epigenetics
Volume8
Issue number1
DOIs
Publication statusPublished - 31 Aug 2016
Externally publishedYes

Bibliographical note

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Keywords

  • gastric cancer
  • H3S10 phosphorylation
  • Resection margin
  • Prognosis
  • p38 MAPK/MSK1 pathway

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