HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance

Journal of Experimental & Clinical Cancer Research

Ming Guo¹  Shiqi Wang²  Zhengyan Li³  Yanxin An⁴  Yongzhan Nie⁵  Qingchuan Zhao⁵  Shuai Xu⁵  Jie Chen⁵  Bin Bai⁵  Kaichun Wu⁵  Dan Song⁵  Xiaotian Song⁵ 

[1] Department of Anesthesiology, Renmin Hospital of Wuhan University, 430060, Wuhan, Hubei Province, China;Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, 710032, Xi’an, Shaanxi Province, China;Department of General Surgery, Center for Minimally Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gao Tan Yan Road, 400038, Chongqing, China;Department of General Surgery, the First Affiliated Hospital of Xi ’an Medical University, No. 48 Fenghao West Road, Lianhu District, 710077, Xi’an, Shaanxi Province, China;State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi’an, Shaanxi Province, China;

关键词: Colorectal cancer;    Metastasis;    PUS7;    HSP90;    LASP1;   

DOI  :  10.1186/s13046-021-01951-5

来源: Springer

【 摘 要 】

BackgroundPseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms.MethodsWe conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry.ResultsOverexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis.ConclusionsThe HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.

【 授权许可】

CC BY