# A20 Facilitates Oxaliplatin Sensitivity in Colorectal Cancer Through Monoubiquitylation of IKK‐β

## TL;DR

This study finds that the enzyme A20 increases sensitivity to the chemotherapy drug oxaliplatin in colorectal cancer by modifying a protein called IKK-β.

## Contribution

The study reveals a new mechanism by which A20 modulates oxaliplatin resistance through monoubiquitylation of IKK-β in colorectal cancer.

## Key findings

- Lower A20 expression correlates with oxaliplatin resistance in colorectal cancer patients.
- A20 monoubiquitylates IKK-β at K163, promoting its degradation and suppressing NF-κB signaling.
- A20 depletion stabilizes IKK-β and induces oxaliplatin resistance in mouse xenografts.

## Abstract

The ubiquitin‐editing enzyme A20 is essential for maintaining inflammatory homeostasis, yet its role in chemoresistance remains unclear. To investigate how A20 regulates oxaliplatin resistance in colorectal cancer (CRC), with a focus on A20‐mediated IKK‐β monoubiquitylation at K163. A prospective, randomized Phase III study is conducted in patients with locally advanced CRC who received either oxaliplatin+capecitabine neoadjuvant chemoradiotherapy (oxaliplatin‐NACRT) or capecitabine‐only neoadjuvant chemoradiotherapy (non‐oxaliplatin‐NACRT). Preoperative biopsy and matched surgical specimens are evaluated by immunohistochemistry to determine A20's association with oxaliplatin response. In oxaliplatin‐NACRT group, patients achieving pathological complete response (pCR) displayed lower A20 expression than non‐pCR patients, whereas no difference is observed in non‐oxaliplatin‐NACRT group. Two additional independent cohorts confirmed A20 downregulation in human CRC tissues, and reduced A20 expression correlated with poorer survival and oxaliplatin resistance. Mechanistically, A20 monoubiquitylates IKK‐β via its fourth zinc‐finger domain, promoting IKK‐β degradation and suppressing NF‐κB nuclear translocation. A20 knockdown or expression of the IKK‐β K163R mutant induced oxaliplatin resistance in mouse xenografts. Clinically, A20 expression are negatively associated with IKK‐β and its downstream targets. A20 depletion promotes oxaliplatin resistance in CRC by stabilizing IKK‐β. the results uncover an essential role of the A20‐IKK‐β axis in oxaliplatin resistance of CRC.

This study demonstrates that the expression of A20, a ubiquitin‐editing enzyme, is positively correlated with oxaliplatin sensitivity in colorectal cancer (CRC). Mechanistically, A20 enhances oxaliplatin sensitivity by inhibiting NF‐κB nuclear translocation through monoubiquitination of IKK‐β. The study identifies the A20–IKK‐β axis as a potential therapeutic target for overcoming oxaliplatin resistance in CRC.