A SP1/MIZ1/MYCN repression complex recruits HDAC1 at the TRKA and p75NTR promoters and affects neuroblastoma malignancy by inhibiting the cell response to NGF.
Neuroblastoma is the most common extracranial solid tumor of childhood. One important factor that predicts a favorable prognosis is the robust expression of the TRKA and p75NTR neurotrophin receptor genes. Interestingly, TRKA and p75NTR expression is often attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and the transcriptional repression of TRKA and p75NTR, but the precise mechanisms involved are unclear. Here, we show that MYCN acts directly to repress TRKA and p75NTR gene transcription. Specifically, we found that MYCN levels were critical for repression and that MYCN targeted proximal/core promoter regions by forming a repression complex with transcription factors SP1 and MIZ1. When bound to the TRKA and p75NTR promoters, MYCN recruited the histone deacetylase HDAC1 to induce a repressed chromatin state. Forced re-expression of endogenous TRKA and p75NTR with exposure to the HDAC inhibitor TSA sensitized neuroblastoma cells to NGF-mediated apoptosis. By directly connecting MYCN to the repression of TRKA and p75NTR, our findings establish a key pathway of clinical pathogenicity and aggressiveness in neuroblastoma.
University of Bologna, Department of Biology, Bologna, Italy.
Nunzio
N
Iraci
Daniel
D
Diolaiti
Antonella
A
Papa
Antonio
A
Porro
Emanuele
E
Valli
Samuele
S
Gherardi
Steffi
S
Herold
Martin
M
Eilers
Roberto
R
Bernardoni
Giuliano
G
Della Valle
Giovanni
G
Perini
D057809:HEK293 Cells; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D051741:Kruppel-Like Transcription Factors; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D016329:Sp1 Transcription Factor; C107961:ZBTB17 protein, human; D020932:Nerve Growth Factor; D020917:Receptor, trkA; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1