Ετικέτες

Τετάρτη 25 Ιανουαρίου 2017

Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

Publication date: 24 January 2017
Source:Cell Reports, Volume 18, Issue 4
Author(s): Dinesh K. Singh, Rahul K. Kollipara, Vamsidara Vemireddy, Xiao-Li Yang, Yuxiao Sun, Nanda Regmi, Stefan Klingler, Kimmo J. Hatanpaa, Jack Raisanen, Steve K. Cho, Shyam Sirasanagandla, Suraj Nannepaga, Sara Piccirillo, Tomoyuki Mashimo, Shan Wang, Caroline G. Humphries, Bruce Mickey, Elizabeth A. Maher, Hongwu Zheng, Ryung S. Kim, Ralf Kittler, Robert M. Bachoo
Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1), which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

Graphical abstract

image

Teaser

Singh et al. report that a set of three transcription factors, Sox2, Olig2, and Zeb1, is an ultimate driver of glioblastoma. These factors are coordinately expressed in glioblastoma, induced by different oncogenic mutations, and their ectopic co-expression can transform immortalized astrocytes.


http://ift.tt/2k0YwHt

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Αναζήτηση αυτού του ιστολογίου