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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-01, Vol.71 (2), p.404-412
• Main Authors: IRACI, Nunzio, DIOLAITI, Daniel, PERINI, Giovanni, PAPA, Antonella, PORRO, Antonio, VALLI, Emanuele, GHERARDI, Samuele, HEROLD, Steffi, EILERS, Martin, BERNARDONI, Roberto, DELLA VALLE, Giuliano
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; HEK293 Cells; HeLa Cells; Histone Deacetylase 1 - metabolism; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Medical sciences; N-Myc Proto-Oncogene Protein; Nerve Growth Factor - pharmacology; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neurology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Pharmacology. Drug treatments; Promoter Regions, Genetic; Protein Structure, Tertiary; Receptor, trkA - biosynthesis; Receptor, trkA - genetics; Receptors, Nerve Growth Factor - biosynthesis; Receptors, Nerve Growth Factor - genetics; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Transcription, Genetic; Transfection; Tumors; Tumors of the nervous system. Phacomatoses
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-2627

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.