MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4

Abstract

Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease.

Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma

“…We further validated synthetic lethality of TFAP4 with MYCN amplification in vitro and in vivo in a range of neuroblastoma cell lines. Our results are consistent with those of Xue et al [ 33 ], who reported that silencing of TFAP4 inhibited proliferation of MYCN -expressing cell lines in vitro.…”

AP4 positively regulates LAPTM4B to promote hepatocellular carcinoma growth and metastasis, while reducing chemotherapy sensitivity

“…Interestingly, LAPTM4B was shown to also regulate AP4 expression via its effects on c‐myc, resulting in a circular positive feedback loop. Although some research has shown that c‐myc works together with AP4 to regulate tumour pathogenesis (Xue et al ., ) or that AP4 regulates the Wnt signalling pathway (Lebensohn et al ., ), which also involves c‐myc, our report is the first to show that AP4 also regulates c‐myc by affecting LAPTM4B expression. As summarized in Fig.…”

Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma

“…TFAP4 belongs to the basic helix-loop-helix-leucine zipper (bHLH-LZ) subgroup of proteins and recognizes the symmetrical DNA core sequence CAGCTG 34 , 35 . Overexpression of TFAP4 promotes neuroblastoma cell growth 36 and induces the epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer 32 . Importantly, it is believed that TFAP4 is involved in maintaining cancer cells in a progenitor-like state 25 , which confers a degree of tumor stemness.…”