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

Fan Luo; Ting Yang; Jiaxin Cao; Qun Chen; Zhenhai Lu; Feiteng Lu; Chaozhuo Lin; Zengfei Xia; Yuanzhong Yang; Peng Li; Wenjuan Ma; Min Luo; Rongxin Zhang

doi:10.1002/advs.202514486

journal article·2026-02Open access

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

Fan Luo, Ting Yang, Jiaxin Cao, Qun Chen, Zhenhai Lu, Feiteng Lu, Chaozhuo Lin, Zengfei Xia, Yuanzhong Yang, Peng Li, Wenjuan Ma, Min Luo, Rongxin Zhang

Advanced Science· Volume 13· Issue 12

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Source abstract

Abstract

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.

Source: crossref · Quality: baseline

Research context

OpenAlex topics: NF-κB Signaling Pathways · Peroxisome Proliferator-Activated Receptors · interferon and immune responses

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Intensive Care Unit State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Department of Clinical Research State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Department of Anesthesiology State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Department of Medical Oncology Fujian Medical University Union Hospital Fuzhou China

Department of Colorectal Surgery State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Department of Experimental Research State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Department of Pathology State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Department of Clinical Laboratory State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Funding

National Natural Science Foundation of China · China Postdoctoral Science Foundation · Natural Science Foundation of Guangdong Province

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