Klin Padiatr 2017; 229(03): 182-195
DOI: 10.1055/s-0037-1602209
Top 3 Solid tumors
Georg Thieme Verlag KG Stuttgart · New York

Phosphotyrosine-Dependent Signaling: the Role of CoREST/REST Transcriptional Repressors in Neuroblastoma

TL Vu-Han
1   Research Institute Children's Cancer Center and Dept. of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
S Buhs
1   Research Institute Children's Cancer Center and Dept. of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
H Gerull
1   Research Institute Children's Cancer Center and Dept. of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
M Horstmann
1   Research Institute Children's Cancer Center and Dept. of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
P Nollau
1   Research Institute Children's Cancer Center and Dept. of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
30 May 2017 (online)

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Introduction:

Neuroblastoma (NB), derived from neuronal precursor cells of the sympathoadrenal lineage, is the most common extracranial, solid tumor in children accounting for approximately 10% of childhood cancer. The clinical course of NB is remarkably heterogeneous, ranging from complete remission without therapeutic intervention to aggressive and fatal courses of disease. Despite significant advances in treatment, the long-term survival of children with high-risk NB remains poor. Several driver mutations such as amplification of MYCN, mutations in ALK, ATRX, ARID1A/B and PTPN11, amplification of LIN28B and TERT rearrangements were identified in NB. However, the relative paucity of recurrent oncogenic mutations in NB suggests that additional mechanism such as epigenetic alterations play important roles in NB development.

Results:

To gain deeper insights in NB signaling, we investigated the state of tyrosine phosphorylation in 21 primary NB by SH2 profiling. Applying SH2 domain pull down and mass spectrometry, we identified over 200 different proteins of which a major subgroup of proteins was functionally associated with RNA processing. Among the different candidate proteins we identified RCOR3 (REST Corepressor 3), a member of the CoREST/REST repressor family. The CoREST/REST complex is well known for its key regulatory role in gene repression during neuronal differentiation mediating demethylation of H3 histone marks by recruitment of the lysine-specific demethylase KDM 1A. Knockdown experiments by siRNA and overexpression of RCOR3 in NB cell lines revealed a significant effect of RCOR3 on cell viability. Moreover, we observed changes in intracellular distribution and phosphorylation of RCOR3 after pervanadate and EGF stimulation, respectively.

Conclusion:

Our current data provide evidence for a novel link between the state of tyrosine phosphorylation, histone modifications and regulation of gene expression in NB.