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Theranostics 2015; 5(1):12-22. doi:10.7150/thno.8799 This issue Cite

Research Paper

Histone H3 Phosphorylation in GBM: a New Rational to Guide the Use of Kinase Inhibitors in anti-GBM Therapy

Romain Pacaud^1,2, Mathilde Cheray^1,2, Arulraj Nadaradjane^1,2, François M. Vallette^1,2,3, Pierre-François Cartron^1,2,3,4✉

1. Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et progression tumorale, Equipe labellisée Ligue Nationale Contre le Cancer. 8 quai moncousu, BP7021, 44007 Nantes, France.
2. Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-4400, Nantes, France.
3. LaBCT, Institut de Cancérologie de l'Ouest, Boulevard J Monod, 44805 Nantes, Saint Herblain Cedex, France.
4. Membre du Réseau Epigénétique du Cancéropôle Grand-Ouest.

✉ Corresponding author: pierre-francois.cartronfr, Institut de Recherche Thérapeutique INSERM U892 - CRCNA, Equipe 9 -Apoptose et Progression tumorale, 8 Quai Moncousu, BP 70721, 44007 Nantes Cedex 1 France, phone: 33-22-808-0327, fax: 33-22-808-0324 More

Abstract

Histones post-translational modifications (PTMs) are crucial components of diverse processes that modulate chromatin. Among the histones PTMs, the histones phosphorylation appears such crucial since it plays a significant role into DNA repair structure, transcription and chromatin compaction during cell division and apoptosis. However, little is known about the prognostic value of the histone phosphorylation in human cancer. This point could be considerate such as an important gap in anti-cancer therapy since the use of adequate kinase inhibitors could remedy to the aberrant histone phosphorylation associated with a poor prognosis factor. To remedy at this situation, we analyzed the phosphorylation level of histone H3 at the residues T3, T6, S10, S28, Y41 and T45 in a collection of 42 glioblastoma multiformes (GBM). Our data indicated that the high level of pH3T6, pH3S10 and pH3Y41 are signatures associated with a poor prognosis of overall survival (OS) of GBM treated with the "temozolomide and irradiation standard" treatment of GBM (named TMZ+Irad treatment). Our data also showed that these signatures are correlated with the high activity of kinases already described as writers of the pH3T6, pH3S10 and pH3Y41 i.e. the PKC, Aurora-B and JAK2, respectively. Finally, our analysis revealed that the use of Enzastaurin, AZD1152, and AZD1480 abrogated the high level of pH3T6, pH3S10 and pH3Y41 while increasing the sensitivity to the “temozolomide and irradiation”-induced cell death. To conclude, it appears that this work provides biomarkers for patient stratification for a therapy including kinase inhibitors.

Keywords: phosphorylation, histone, epigenetic, glioma, apoptosis

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