# MDM2 promotes CELF6 ubiquitination-dependent degradation to promote neuroblastoma cell proliferation

## TL;DR

This study shows that MDM2 helps destroy the CELF6 protein through ubiquitination, which promotes the growth of neuroblastoma cells.

## Contribution

The novel finding is that MDM2 regulates CELF6 stability via ubiquitination, linking it to neuroblastoma proliferation.

## Key findings

- High CELF6 expression correlates with better prognosis in neuroblastoma.
- MDM2 promotes CELF6 degradation through K48-linked ubiquitination.
- MDM2-driven proliferation of neuroblastoma cells depends on CELF6 depletion.

## Abstract

The ubiquitin–proteasome system plays a crucial role in neuroblastoma progression, yet the regulation of key degradation targets remains incompletely understood. By integrating transcriptomic and proteomic data, we identified nine candidate proteins, including CELF6, whose degradation is potentially mediated by ubiquitination. Survival analyses revealed that high CELF6 expression correlated with a favorable prognosis. Functional assays demonstrated that CELF6 suppresses neuroblastoma cell proliferation without affecting apoptosis. Mechanistically, the E3 ubiquitin ligase MDM2 directly interacts with CELF6, promoting its degradation via K48-linked ubiquitination. MDM2 overexpression accelerates CELF6 degradation, while its inhibition stabilizes CELF6 protein levels, an effect reversed by proteasome inhibitors. Furthermore, MDM2-driven neuroblastoma cell proliferation is dependent on CELF6 depletion. These findings establish MDM2 as a key regulator of CELF6 stability and highlight the MDM2–CELF6 axis as a potential therapeutic target in neuroblastoma.