KLF7 promotes neuroblastoma differentiation through the GTPase signaling pathway by upregulating neuroblast differentiation‐associated protein AHNAKs and glycerophosphodiesterase GDPD5

The arrest of neural crest‐derived sympathoadrenal neuroblast differentiation contributes to neuroblastoma formation, and overriding this blocked differentiation is a clear strategy for treating high‐risk neuroblastoma. A better understanding of neuroblast or neuroblastoma differentiation is essential for developing new therapeutic approaches. It has been proposed that Krueppel‐like factor 7 (KLF7) is a neuroblastoma super‐enhancer‐associated transcription factor gene. Moreover, KLF7 was found to be intensely active in postmitotic neuroblasts of the developing nervous system during embryogenesis. However, the role of KLF7 in the differentiation of neuroblast or neuroblastoma is unknown. Here, we find a strong association between high KLF7 expression and favorable clinical outcomes in neuroblastoma. KLF7 induces differentiation of neuroblastoma cells independently of the retinoic acid (RA) pathway and acts cooperatively with RA to induce neuroblastoma differentiation. KLF7 alters the GTPase activity and multiple differentiation‐related genes by binding directly to the promoters of neuroblast differentiation‐associated protein (AHNAK and AHNAK2) and glycerophosphodiester phosphodiesterase domain‐containing protein 5 (GDPD5) and regulating their expression. Furthermore, we also observe that silencing KLF7 in neuroblastoma cells promotes the adrenergic‐to‐mesenchymal transition accompanied by changes in enhancer‐mediated gene expression. Our results reveal that KLF7 is an inducer of neuroblast or neuroblastoma differentiation with prognostic significance and potential therapeutic value. KLF7 binds directly to the promoters of neuroblast differentiation‐associated proteins (AHNAK and AHNAK2) and GDPD5 and regulates their expression to influence the GTPase activity, subsequently inducing neuroblastoma differentiation. Depletion of KLF7 in neuroblastoma cells promotes the adrenergic‐to‐mesenchymal transition accompanied by changes in enhancer‐mediated gene expression.