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Super-enhancer-driven TCF4 promotes neuroblastoma metastasis by mediating GM3 synthesis [ChIP-seq]

ABSTRACT: Metastasis remains a critical factor for survival in neuroblastoma (NB). 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. These findings reveal an epitranscriptomic-metabolic axis governing NB metastasis and propose ACY-1215 as a translational therapeutic candidate for clinical intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303303 | GEO | 2026/05/27

REPOSITORIES: GEO

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Project description:Background: Abdominal aortic aneurysm (AAA) is a potentially life-threatening condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipids metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis which is an important risk factor for AAA, but the potential contribution of GM3 to AAA development has not been investigated. Methods: We performed a metabolomics study to evaluated GM3 level in plasma of human AAA patients. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through western blotting and immunofluorescence staining. RNA sequencing, proteomic analysis, affinity purification and mass spectrometry, surface plasmon resonance (SPR) analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA. Results: We found significantly reduced plasma levels of the GM3 in human AAA patients. GM3 content and ST3GAL5 expression were all decreased in abdominal aortic VSMCs in AAA patients and mouse model. RNA-sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs (HASMCs) induced ferroptosis. Importantly, we showed that GM3 interacted directly with the extracellular domain of transferrin receptor 1 (TFR1), a cell membrane protein critical for cellular iron uptake, disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development, while GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic VSMCs and markedly decreased AAA incidence. Conclusions: Together, these results suggest that GM3 dysregulation promotes ferroptosis of VSMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for the treatment of AAA.

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Super-enhancer-driven TCF4 promotes neuroblastoma metastasis by mediating GM3 synthesis [ChIP-seq]

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