Pacaud Romain, Cheray Mathilde, Nadaradjane Arulraj, Vallette François M, Cartron Pierre-François
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.
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.
Theranostics. 2015 Jan 1;5(1):12-22. doi: 10.7150/thno.8799. eCollection 2015.
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.
组蛋白翻译后修饰（PTMs）是调节染色质的多种过程的关键组成部分。在组蛋白PTMs中，组蛋白磷酸化显得尤为关键，因为它在细胞分裂和凋亡过程中的DNA修复结构、转录和染色质压缩中发挥着重要作用。然而，关于组蛋白磷酸化在人类癌症中的预后价值知之甚少。鉴于使用适当的激酶抑制剂可以纠正与不良预后因素相关的异常组蛋白磷酸化，这一点可被视为抗癌治疗中的一个重要空白。为了改善这种情况，我们分析了42例多形性胶质母细胞瘤（GBM）样本中组蛋白H3在T3、T6、S10、S28、Y41和T45位点的磷酸化水平。我们的数据表明，pH3T6、pH3S10和pH3Y41的高水平是与接受“替莫唑胺和放疗标准”治疗（称为TMZ+Irad治疗）的GBM总生存期（OS）不良预后相关的特征。我们的数据还表明，这些特征分别与已被描述为pH3T6、pH3S10和pH3Y41的书写酶的激酶的高活性相关，即PKC、Aurora - B和JAK2。最后，我们的分析表明，使用恩扎妥林、AZD1152和AZD1480可消除pH3T6、pH3S10和pH3Y41的高水平，同时增加对“替莫唑胺和放疗”诱导的细胞死亡的敏感性。总之，这项工作似乎为包括激酶抑制剂在内的治疗的患者分层提供了生物标志物。
