Taken together, the present study (i) identifies low-level CD9 expression as a novel prognostic marker in high-risk neuroblastoma patient subgroups, (ii) exposes CD9 transcriptional activation by GRHL1 and its repression by MYCN and HDAC5, (iii) defines the potential of high-level CD9 expression to interrupt the neuroblastoma invasion-metastatic cascade and (iv) demonstrates the indirect druggability of CD9 by combined inhibition of HDAC5 and DNA methyltransferase inhibitors. This evidence concerns the gene GRHL1 and neuroblastoma.