PMID- 28671673
OWN - NLM
STAT- MEDLINE
DCOM- 20171102
LR  - 20210513
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 43
DP  - 2017 Oct 26
TI  - EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal 
      autoregulatory feedback in Ewing sarcoma.
PG  - 5995-6005
LID - 10.1038/onc.2017.202 [doi]
AB  - Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. 
      Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically 
      regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, 
      we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in 
      cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the 
      activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, 
      affecting the expression of a large number of EWS-FLI1-anticorrelated genes 
      including structural and regulatory cytoskeletal genes. Consistent with this 
      finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong 
      overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 
      chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of 
      the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of 
      TEAD-binding motifs in these shared genomic binding regions and overlapping 
      transcriptional footprints of MRTFB and TEAD factors led us to propose synergy 
      between MRTFB and the YAP/TEAD complex in the regulation of 
      EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin 
      pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which 
      directly affects the actin-autoregulatory feedback loop. As spontaneous 
      fluctuations in EWS-FLI1 levels of Ewing sarcoma cells in vitro and in vivo, 
      associated with a switch between a proliferative, non-migratory EWS-FLI1-high and 
      a non-proliferative highly migratory EWS-FLI1-low state, were recently described, 
      our data provide a mechanistic basis for the underlying EWS-FLI1-dependent 
      reversible cytoskeletal reprogramming of Ewing sarcoma cells.
FAU - Katschnig, A M
AU  - Katschnig AM
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
FAU - Kauer, M O
AU  - Kauer MO
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
FAU - Schwentner, R
AU  - Schwentner R
AUID- ORCID: 0000-0001-6839-0322
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
FAU - Tomazou, E M
AU  - Tomazou EM
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
FAU - Mutz, C N
AU  - Mutz CN
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
FAU - Linder, M
AU  - Linder M
AD  - Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
FAU - Sibilia, M
AU  - Sibilia M
AD  - Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
FAU - Alonso, J
AU  - Alonso J
AUID- ORCID: 0000-0002-6287-8391
AD  - Unidad de Tumores Solidos Infantiles, Instituto de Investigacion de Enfermedades 
      Raras, Madrid, Spain.
FAU - Aryee, D N T
AU  - Aryee DNT
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
AD  - Department of Paediatrics, Medical University Vienna, Vienna, Austria.
FAU - Kovar, H
AU  - Kovar H
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, 
      Austria.
AD  - Department of Paediatrics, Medical University Vienna, Vienna, Austria.
LA  - eng
GR  - V 506/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170703
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Actins)
RN  - 0 (Chromatin)
RN  - 0 (EWS-FLI fusion protein)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Proto-Oncogene Protein c-fli-1)
RN  - 0 (RNA-Binding Protein EWS)
SB  - IM
MH  - Actins/genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Cellular Reprogramming/*genetics
MH  - Chromatin/genetics
MH  - Cytoskeleton/*genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Oncogene Proteins, Fusion/*genetics
MH  - Proto-Oncogene Protein c-fli-1/*genetics
MH  - RNA-Binding Protein EWS/*genetics
MH  - Sarcoma, Ewing/*genetics/pathology
MH  - Signal Transduction/genetics
PMC - PMC5666320
COIS- The authors declare no conflict of interest.
EDAT- 2017/07/04 06:00
MHDA- 2017/11/03 06:00
PMCR- 2017/11/02
CRDT- 2017/07/04 06:00
PHST- 2017/02/28 00:00 [received]
PHST- 2017/05/19 00:00 [revised]
PHST- 2017/05/22 00:00 [accepted]
PHST- 2017/07/04 06:00 [pubmed]
PHST- 2017/11/03 06:00 [medline]
PHST- 2017/07/04 06:00 [entrez]
PHST- 2017/11/02 00:00 [pmc-release]
AID - onc2017202 [pii]
AID - 10.1038/onc.2017.202 [doi]
PST - ppublish
SO  - Oncogene. 2017 Oct 26;36(43):5995-6005. doi: 10.1038/onc.2017.202. Epub 2017 Jul 
      3.