Entry of ZSWIM4 to the nucleus is crucial for its inhibition of KIT and BMAL1 in gastrointestinal stromal tumors

Xu Cao; Jinhai Tian; Man Yee Cheung; Liangying Zhang; Zimei Liu; Zongying Jiang; Shaoting Zhang; Kun Xiao; Sien Zhao; Ming Wang; Feng Ding; Shujing Li; Lijun Ma; Hui Zhao; Jianmin Sun

doi:10.1186/s13578-024-01271-z

Entry of ZSWIM4 to the nucleus is crucial for its inhibition of KIT and BMAL1 in gastrointestinal stromal tumors

Cell Biosci. 2024 Jun 29;14(1):87. doi: 10.1186/s13578-024-01271-z.

Authors

Xu Cao¹, Jinhai Tian¹, Man Yee Cheung², Liangying Zhang¹, Zimei Liu³, Zongying Jiang^{1

4}, Shaoting Zhang¹, Kun Xiao¹, Sien Zhao¹, Ming Wang¹, Feng Ding¹, Shujing Li^{1

4}, Lijun Ma⁵, Hui Zhao^{6

7

8}, Jianmin Sun⁹

Affiliations

¹ NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
² Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
³ Department of Oncology, School of Medicine, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁴ The General Hospital of Ningxia Medical University, Yinchuan, China.
⁵ Department of Oncology, School of Medicine, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China. 732001971@shsmu.edu.cn.
⁶ Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. zhaohui@cuhk.edu.hk.
⁷ Kunming Institute of Zoology - The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases, The Chinese University of Hong Kong, Hong Kong SAR, China. zhaohui@cuhk.edu.hk.
⁸ Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics, The Chinese University of Hong Kong, Hong Kong SAR, China. zhaohui@cuhk.edu.hk.
⁹ NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. jianmin.sun@nxmu.edu.cn.

Abstract

Background: Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs).

Results: We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KIT^V558A/WT mice and KIT^V558A/WT/ZSWIM4^-/- mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KIT^V558A/WT mice.

Conclusions: Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.

Keywords: BMAL1; GISTs; KIT; Signaling; ZSWIM4.

Abstract

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