Super-enhancer-driven TCF4 promotes neuroblastoma metastasis by mediating GM3 synthesis [CUT&Tag]

Although NB metastasis involves multifaceted regulatory mechanisms, the role of epitranscriptomic regulation in this process has not been elucidated. Here, we identify super-enhancer-driven transcription factor TCF4 as a central orchestrator of metastatic networks in NB, promoting both in vitro and in vivo dissemination.

Mechanistically, TCF4 transcriptionally activates SPTLC1, a pivotal enzyme in sphingolipid biosynthesis, to promote ganglioside GM3 synthesis. GM3 orchestrates membrane architecture remodeling, thereby modulating ITGB1 membrame localization and activation, which subsequently potentiates metastasis-associated FAK signaling. Notably, we demonstrate that the HDAC6 inhibitor ACY-1215 suppresses NB malignancy by destabilizing TCF4 protein.