SAE1 promotes tumor cell malignancy <i>via</i> SUMOylation and liquid-liquid phase separation facilitated nuclear export of p27.

Ling WANG; Jie MIN; Jinjun QIAN; Xiaofang HUANG; Xichao YU; Yuhao CAO; Shanliang SUN; Mengying KE; Xinyu LV; Wenfeng SU; Mengjie GUO; Nianguang LI; Shiqian QI; Hongming HUANG; Chunyan GU; Ye YANG

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SAE1 promotes tumor cell malignancy via SUMOylation and liquid-liquid phase separation facilitated nuclear export of p27.

Author: Ling WANG ¹ ; Jie MIN ² ; Jinjun QIAN ² ; Xiaofang HUANG ³ ; Xichao YU ² ; Yuhao CAO ² ; Shanliang SUN ⁴ ; Mengying KE ² ; Xinyu LV ² ; Wenfeng SU ¹ ; Mengjie GUO ² ; Nianguang LI ⁴ ; Shiqian QI ³ ; Hongming HUANG ¹ ; Chunyan GU ² ; Ye YANG ¹
Author Information

1. Department of Hematology, Affiliated Hospital of Nantong University, Nantong 226001, China.
2. School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
3. Department of Urology, Institute of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, and National Collaborative Innovation Center, Chengdu 610041, China.
4. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Publication Type:Journal Article
Keywords: Cancer; Colchicine; Liquid–liquid phase separation; Multiple myeloma; Post-translational modifications; SAE1; SUMOylation; p27
From: Acta Pharmaceutica Sinica B 2025;15(4):1991-2007
CountryChina
Language:English
Abstract: Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.