2. Academic Validation
  3. IMPDH1/YB-1 Positive Feedback Loop Assembles Cytoophidia and Represents a Therapeutic Target in Metastatic Tumors

IMPDH1/YB-1 Positive Feedback Loop Assembles Cytoophidia and Represents a Therapeutic Target in Metastatic Tumors

  • Mol Ther. 2020 May 6;28(5):1299-1313. doi: 10.1016/j.ymthe.2020.03.001.
Hailong Ruan 1,  Zhengshuai Song 1,  Qi Cao 1,  Dong Ni 1,  Tianbo Xu 1,  Keshan Wang 1,  Lin Bao 1,  Junwei Tong 1,  Haibing Xiao 1,  Wen Xiao 1,  Gong Cheng 1,  Zhiyong Xiong 1,  Huageng Liang 1,  Di Liu 1,  Liang Wang 1,  Tredan Olivier 2,  Boyle Helen Jane 2,  Hongmei Yang 3,  Xiaoping Zhang 4,  Ke Chen 5
Affiliations

Affiliations

  • 1 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 Department of Oncology, Centre Leon Berard, 28 Prom. Léa et Napoléon Bullukian, 69008 Lyon, France.
  • 3 Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: xzhang@hust.edu.cn.
  • 5 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: shenke@hust.edu.cn.
PMID: 32209435 DOI: 10.1016/j.ymthe.2020.03.001
Abstract

Recently, cytoophidium, a nonmembrane-bound intracellular polymeric structure, has been shown to exist in various organisms, including tumor tissues, but its function and mechanism have not yet been examined. Examination of cytoophidia-assembled gene inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase (CTPS) mRNA levels showed that only IMPDH1 levels were significantly higher in the clear cell renal cell carcinoma (ccRCC). IMPDH1 was positively correlated with the metastasis-related gene Y-box binding protein 1 (YB-1) and served as an independent prognostic factor in ccRCC. Kaplan-Meier analysis indicated that patients with tumors that expressed high IMPDH1 levels had a shorter overall survival (OS) and disease-free survival (DFS). Furthermore, detection of cytoophidia by immunofluorescence staining in ccRCC tissues showed that IMPDH1-assembled cytoophidia are positively associated with tumor metastasis. Mechanistically, IMPDH1 and YB-1 formed an autoregulatory positive feedback loop: IMPDH1 maintained YB-1 protein stabilization; YB-1 induced IMPDH1 expression by binding to the IMPDH1 promoter motif. Functionally, IMPDH1-assembled cytoophidia physically interacted with YB-1 and translocated YB-1 into the cell nucleus, thus correlating with ccRCC metastasis. Our findings provide the first solid theoretical rationale for targeting the IMPDH1/YB-1 axis to improve metastatic renal Cancer treatment.

Keywords

IMPDH1; YB-1; ccRCC; clear cell renal cell carcinoma; cytoophidia; metastasis.

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