XAF1 promotes colorectal cancer metastasis via VCP–RNF114–JUP axis

Author:

Xia Ji1ORCID,Ma Ning2ORCID,Shi Qian3ORCID,Liu Qin-Cheng4ORCID,Zhang Wei4ORCID,Cao Hui-Jun1ORCID,Wang Yi-Kang1ORCID,Zheng Qian-Wen15ORCID,Ni Qian-Zhi1ORCID,Xu Sheng1ORCID,Zhu Bing1ORCID,Qiu Xiao-Song15ORCID,Ding Kai1ORCID,Huang Jing-Yi1ORCID,Liang Xin1ORCID,Chen Yu1ORCID,Xiang Yan-Jun6ORCID,Zhang Xi-Ran1ORCID,Qiu Lin1ORCID,Chen Wei7ORCID,Xie Dong158ORCID,Wang Xiang9ORCID,Long Lingyun1ORCID,Li Jing-Jing18ORCID

Affiliation:

1. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences 1 , Shanghai, China

2. Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine 2 Department of Thoracic Surgery, , Shanghai, China

3. Central Laboratory, The First Affiliated Hospital of Huzhou University 3 , Huzhou, China

4. Fengxian Hospital Affiliated to Southern Medical University 4 Department of General Surgery, , Shanghai, China

5. School of Life Science and Technology, ShanghaiTech University 5 , Shanghai, China

6. Eastern Hepatobiliary Surgery Hospital, Naval Medical University 6 Department of Hepatic Surgery VI, , Shanghai, China

7. Institute of Clinical Medicine Research, Zhejiang Provincial People’s Hospital, Hangzhou Medical College 7 , Hangzhou, China

8. NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment 8 , Beijing, China

9. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province. Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine 9 , Hangzhou, China

Abstract

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1–VCP–RNF114–JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1–VCP–RNF114–JUP axis is a potential therapeutic target for CRC treatment.

Funder

National Natural Science Foundation of China

Youth Innovation Promotion Association of Chinese Academy of Sciences

Sanofi-SIBS

Natural Science Foundation of Shanghai

Publisher

Rockefeller University Press

Subject

Cell Biology

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