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

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation

“…The RAC1 short-3' UTR isoform promotes the oncogenic and metastatic capacities in urothelial bladder carcinoma cells both in vitro and in vivo [ 21 ]. Treatment with 200 nM MBQ-167, a RAC1 inhibitor, limited the enhanced migration, invasion, and filopodia formation resulting from KDM6A depletion in T24 cells [ 22 ]. The findings above suggest that the movement of bladder cancer cells is at least partially dependent on the activity of RAC1.…”

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…A comparable situation can be underlined in bladder cancer. Rac1 is a major player of the metastasis of bladder cancer [ 109 ]. The invasion and migration of bladder cancer cells depend, to some extent, on the activation status of Rac1 and the activity of its regulators, notably the aforementioned Rac1-binding protein aldoketo reductase 1C1 (AKR1C1), up-regulated in metastatic human bladder cancer specimens.…”

FOXA1 Leads to Aberrant Expression of SIX4 Affecting Cervical Cancer Cell Growth and Chemoresistance

“…FOXA1 has been documented to bind to the promoter of KDM6A and PLOD2, thus promoting their transcription in bladder cancer and non-small-cell lung cancer, respectively [ 23 , 24 ]. Similarly, in CC, FOXA1 was verified to activate the transcription of LINC00662 and PDK4 [ 25 ].…”