Tyrosine hydroxylase/catecholamine signaling pathway promotes high-risk neuroblastoma growth by upregulating MYCN

Neuroblastoma (NB) is an aggressive pediatric cancer with poor high‑risk prognosis. MYCN amplification ( MNA ) is an established high-risk biomarker but is present in only approximately 20% of patients. Consistent with recent studies, our results showed that high MYCN expression, observed in approximately 60% of high-risk patients, serves as a more prevalent biomarker for high-risk NB, although its upstream regulatory mechanism remains incompletely understood. The transcript level of tyrosine hydroxylase (TH), a key enzyme in catecholamine synthesis, is markedly elevated in high-risk NB patients and correlates with poor prognosis. We found that TH and MYCN expression were strongly co-expressed and enriched in high‑risk NB. Functional assays demonstrated that TH promotes NB cell proliferation, migration, invasion, and tumor growth through transcriptional upregulation of MYCN. Mechanistically, TH-derived catecholamines activate the β2-AR–ERK pathway, leading to increased SP1 protein levels and CREB1 phosphorylation. Notably, we identified CREB1 as a novel transcription factor that directly binds the MYCN promoter. Importantly, co‑inhibition of SP1 and CREB1 substantially downregulates MYCN and suppresses tumor growth in vitro and in vivo. Collectively, our study reveals a critical mechanism underlying MYCN dysregulation and highlights the TH–catecholamine–β2-AR–ERK–SP1/CREB1 axis as a promising therapeutic target for high-risk NB.