KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

Molecular Cancer

Shuna Sun¹  Yajing Zhao²  Lei Liu³  Jianfeng Cui³  Lipeng Chen³  Shouzhen Chen³  Yangyang Xia³  Yong Wang³  Benkang Shi⁴  Yongxin Zou⁵  Xiaochen Liu⁵ 

[1] Department of Dermatology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong Provincial Hospital of Traditional Chinese Medicine, Jinan, China;Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China;Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China;Key Laboratory for Experimental Teratology of Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China;Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong, Jinan, China;Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China;Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong, Jinan, China;Key Laboratory for Experimental Teratology of Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China;

关键词: Bladder cancer;    Metastasis;    Epigenetics;    KDM6A;    ARHGDIB-Rac1 axis;    FOXA1;   

DOI  :  10.1186/s12943-021-01369-9

来源: Springer

【 摘 要 】

BackgroundKDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown.MethodsTissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A.ResultsWe showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential.ConclusionOur findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.

【 授权许可】

CC BY