DNAJC12 downregulation induces neuroblastoma progression via increased histone H4K5 lactylation

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite treatment advances, the survival rates of high-risk NB patients remain low. This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies. In this study, we demonstrated that the reduced levels of DNAJC12, a protein involved in metabolic regulation, are associated with poor prognosis in NB patients. Our data indicate that low DNAJC12 expression activates glycolysis in NB cells, leading to increased lactic acid production and histone H4 lysine 5 lactylation (H4K5la). Elevated H4K5la upregulates the transcription of COL1A1, a gene implicated in cell metastasis. Immunohistochemistry staining of NB patient samples confirmed that high H4K5la levels correlate with poor clinical outcomes. Furthermore, we showed that inhibiting glycolysis, reducing H4K5la, or targeting COL1A1 can mitigate the invasive behavior of NB cells. These findings reveal a critical link between metabolic reprogramming and epigenetic modifications in the context of NB progression, suggesting that H4K5la could serve as a novel diagnostic and prognostic marker, and shed light on identifying new therapeutic targets within metabolic pathways for the treatment of this aggressive pediatric cancer.