KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1.
KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1.
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KDM6A-ARHGDIB轴通过抑制Rac1阻断膀胱癌的转移
DOI：
10.1186/s12943-021-01369-9
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发表时间：
2021-05-18
期刊：
影响因子：
37.3
通讯作者：
Zou Y
中科院分区：
文献类型：
--
作者：
Liu L;Cui J;Zhao Y;Liu X;Chen L;Xia Y;Wang Y;Chen S;Sun S;Shi B;Zou Y
KDM 6A是一种组蛋白去甲基化酶，在膀胱癌（BCa）中经常发生突变。然而，KDM 6A在膀胱癌进展中的作用和详细的分子机制仍然未知。使用组织标本来确定KDM 6A和ARHGDIB的表达水平和预后价值。采用MTT法、集落形成法、创伤愈合法和Transwell迁移侵袭实验分别检测BCa细胞增殖、迁移和侵袭能力。巨噬细胞的趋化性用于评估KDM 6A募集巨噬细胞的能力。皮下肿瘤模型和裸鼠中的尾静脉肿瘤注射用于评估KDM 6A在体内的作用。通过RNA测序、qPCR、Western blot、ChIP和鬼笔环肽染色等方法研究KDM 6A的分子功能。采用双荧光素酶报告基因检测KDM 6A和FOXA 1对ARHGDIB和KDM 6A启动子的影响。我们发现KDM 6A抑制BCa细胞的运动性和侵袭性。在机制上，KDM 6A通过使组蛋白H3赖氨酸二/三甲基化（H3 K27 me 2/3）去甲基化来促进ARHGDIB的转录，并因此导致Rac 1的抑制。催化H3 K27甲基化的EZH 2起到沉默ARHGDIB表达的作用，并且EZH 2抑制剂可以中和由KDM 6A缺陷引起的转移效应。此外，我们证明FOXA 1直接结合KDM 6A启动子，从而反式激活KDM 6A，导致转移潜力降低。我们的研究结果确立了FOXA 1-KDM 6A-ARHGDIB轴在抑制BCa恶性肿瘤中的关键作用，并将KDM 6A和EZH 2确定为BCa管理中的潜在治疗靶点。在线版本包含补充材料，可通过10.1186/s12943-021-01369-9获得。
KDM6A, 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. Tissue 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. We 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. Our 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. The online version contains supplementary material available at 10.1186/s12943-021-01369-9.
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