Oral Presentation Advances in Neuroblastoma Research Congress 2016

SOX11 acts as part of the MYCN regulatory protein complex implicated in neuroblastoma (#5)

Bieke Decaesteker 1 2 , Sara De Brouwer 1 2 , Suzanne Vanhauwaert 1 2 , Fanny De Vloed 1 2 , Anneleen Beckers 1 2 , Genevieve Laureys 3 , Stein Aerts 4 , Sara Ek 5 , Frank Speleman 1 2 , Katleen De Preter 1 2
  1. Center for Medical Genetics, Ghent University, Ghent, Belgium
  2. Cancer Research Institute Ghent (CRIG), Ghent University, Ghent
  3. Department of Pediatric Hematology and Oncology, Ghent University Hospital, Ghent, Belgium
  4. Center for Human Genetics, Faculty of Medicine KUL, Leuven, Belgium
  5. Department of Immunotechnology, Lund University, Lund, Sweden

The high expression levels of the SRY-related HMG-box transcription factor 11 (SOX11) in neuroblastoma, frequent copy number gain and occasional focal amplification, and expression in developing sympathetic nervous system, suggested a role for SOX11 as lineage survival oncogene and prompted us to further investigate its role in MYCN driven neuroblastoma formation.

First, we observed a strong correlation with MYCN expression levels (R=0.576, p=1.9E-26) and high SOX11 expression was indicative for poor prognosis. In vitro SOX11 knock down experiments showed amongst others reduced colony formation capacity and G1-S phase cell growth arrest, in conjunction with decreased MYCN mRNA levels. Moreover, both in cell lines with in vitro MYCN induction and MYCN overexpressing mouse neuroblastoma models, SOX11 was significantly increased, suggesting the existence of a SOX11 - MYCN regulatory loop. SOX11 and H3K27ac ChIP-sequencing revealed that more than half (62%) of the SOX11 binding sites were at enhancers while 19% of SOX11 targets contained an E-Box motif, typically known to be targeted by MYCN, in keeping with an observed overlap of 30% of SOX11 and MYCN binding targets. Next, we demonstrated close physical proximity/interaction between SOX11 and MYCN proteins using both proximity-ligation as well as co-immunoprecipitation assays.

To further evaluate in vivo effects of SOX11 overexpression in sympathetic progenitor cells, we established a zebrafish and mouse dbh-SOX11 model and are performing crossing with the previously established dbh-MYCN animal models to evaluate SOX11 cooperative accelerated tumour formation.