Dussaussois-Montagne Audrey, Jaillet Jérôme, Babin Laetitia, Verrelle Pierre, Karayan-Tapon Lucie, Renault Sylvaine, Rousselot-Denis Cécilia, Zemmoura Ilyess, Augé-Gouillou Corinne
EA 6306 IGC, University François Rabelais, 37200 Tours, France.
UMR CNRS 7292 GICC, University François Rabelais, 37000 Tours, France.
Oncotarget. 2017 Feb 7;8(6):9835-9848. doi: 10.18632/oncotarget.14218.
Glioblastomas (GBMs) are the most frequent and the most aggressive brain tumors, known for their chemo- and radio-resistance, making them often incurable. We also know that SETMAR is a protein involved in chromatin dynamics and genome plasticity, of which overexpression confers chemo- and radio-resistance to some tumors. The relationships between SETMAR and GBM have never been explored. To fill this gap, we define the SETMAR status of 44 resected tumors and of GBM derived cells, at both the mRNA and the protein levels. We identify a new, small SETMAR protein (so called SETMAR-1200), enriched in GBMs and GBM stem cells as compared to the regular enzyme (SETMAR-2100). We show that SETMAR-1200 is able to increase DNA repair by non-homologous end-joining, albeit with a lower efficiency than the regular SETMAR protein. Interestingly, the regular/small ratio of SETMAR in GBM cells changes depending on cell type, providing evidence that SETMAR expression is regulated by alternative splicing. We also demonstrate that SETMAR expression can be regulated by the use of an alternative ATG. In conclusion, various SETMAR proteins can be synthesized in human GBM that may each have specific biophysical and/or biochemical properties and characteristics. Among them, the small SETMAR may play a role in GBMs biogenesis. On this basis, we would like to consider SETMAR-1200 as a new potential therapeutic target to investigate, in addition to the regular SETMAR protein already considered by others.
胶质母细胞瘤（GBM）是最常见且侵袭性最强的脑肿瘤，以其对化疗和放疗的抗性而闻名，这使得它们常常无法治愈。我们还知道，SETMAR是一种参与染色质动态变化和基因组可塑性的蛋白质，其过表达赋予某些肿瘤化疗和放疗抗性。SETMAR与GBM之间的关系从未被探究过。为了填补这一空白，我们在mRNA和蛋白质水平上定义了44个切除肿瘤及GBM衍生细胞的SETMAR状态。我们鉴定出一种新的、较小的SETMAR蛋白（即所谓的SETMAR-1200），与常规酶（SETMAR-2100）相比，它在GBM和GBM干细胞中更为富集。我们表明，SETMAR-1200能够通过非同源末端连接增加DNA修复，尽管效率低于常规的SETMAR蛋白。有趣的是，GBM细胞中SETMAR的常规/小蛋白比例因细胞类型而异，这证明SETMAR的表达受可变剪接调控。我们还证明，SETMAR的表达可通过使用替代的起始密码子来调控。总之，人类GBM中可以合成各种SETMAR蛋白，它们可能各自具有特定的生物物理和/或生化特性。其中，较小的SETMAR可能在GBM的发生过程中起作用。在此基础上，除了其他人已经考虑的常规SETMAR蛋白外，我们希望将SETMAR-1200视为一个新的潜在治疗靶点进行研究。
