Valproate Releases the Latent Differentiation Capacity of Neuroblastoma by Targeting SP1/CDK4 Signaling

Differentiation therapy represents a standard therapeutic regimen for high-risk neuroblastoma (HR-NB), demonstrating significant efficacy in suppressing tumor recurrence and improving patient survival rates. Retinoic acid (RA) remains the sole clinically approved differentiation-inducing agent for HR-NB, yet its therapeutic application is substantially limited by inherent drug resistance. Here, we found that valproate (VPA) exhibited dose-dependent inhibition of tumorigenicity in NB cells SH-SY5Y, SK-N-BE and retinoic acid (RA)-resistant SK-N-AS, along with the induction of G1-phase arrest and extensive neuronal differentiation. Subsequently, the transcriptomic landscape revealed that the impact of VPA on the biological processes of NB cells was predominantly enriched in the cell cycle pathway and Cyclin Dependent Kinase 4 (CDK4) as the most central gene. Additionally, we found that dual treatment with all-trans retinoic acid (ATRA) synergistically promotes NB cell differentiation, specifically in RA-resistant SK-N-AS cells. We therefore identify VPA as a therapeutic approach to dramatically enhance NB differentiation efficacy that could be used in combination with RA to improve patient outcomes, specifically for patients with RA-resistant HR-NB. These investigations will provide novel insights into cell cycle-mediated differentiation reprogramming in HR-NB.