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Ten-Eleven-Translocation 5-methylcytosine dioxygenases 1–3 (TET1-3) convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), using oxygen as a co-substrate. Contrary to expectations, hypoxia induces 5-hmC gains in  MYCN -amplified neuroblastoma (NB) cells via upregulation of  TET1 . Here, we show that MYCN directly controls  TET1  expression in normoxia, and in hypoxia, HIF-1 augments  TET1  expression and TET1 protein stability. Through gene-editing, we identify two MYCN and HIF-1 binding sites within  TET1  that regulate gene expression. Bioinformatic analyses of 5-hmC distribution and RNA-sequencing data from hypoxic cells implicate hypoxia-regulated genes important for cell migration, including  CXCR4 . We show that hypoxic cells lacking the two MYCN/HIF-1 binding sites within  TET1  migrate slower than controls. Treatment of  MYCN- amplified NB cells with a CXCR4 antagonist results in slower migration under hypoxic conditions, suggesting that inclusion of a CXCR4 antagonist into NB treatment regimens could be beneficial for children with  MYCN- amplified NBs.

MYCN and HIF-1 directly regulate TET1 expression to control 5-hmC gains and enhance neuroblastoma cell migration in hypoxia