XIAP RING domain mediates miR-4295 expression and subsequently inhibiting p63α protein translation and promoting transformation of bladder epithelial cells

Abstract

The X-linked inhibitor of apoptosis protein (XIAP) contains three N-terminal BIR domains that mediate anti-apoptosis and one C-terminal RING finger domain whose function(s) are not fully defined. Here we show that the RING domain of XIAP strongly inhibits the expression of p63α, a known tumor suppressor. XIAP knockdown in urothelial cells or RING deletion in knockin mice markedly upregulates p63α expression. This RING-mediated p63α downregulation is critical for the malignant transformation of normal urothelial cells following EGF treatment. We further show that the RING domain promotes Sp1-mediated transcription of miR-4295 which targets the 3′UTR of p63α mRNA and consequently inhibits p63α translation. Our results reveal a previously unknown function of the RING of XIAP in promoting miR-4295 transcription, thereby reducing p63α translation and enhancing urothelial transformation. Our data offer novel insights into the multifunctional effects of the XIAP RING domain on urothelial tumorigenesis and the potential for targeting this frequently overexpressed protein as a therapeutic alternative.

XIAP overexpression promotes bladder cancer invasion in vitro and lung metastasis in vivo via enhancing nucleolin‐mediated Rho‐GDIβ mRNA stability

“…h and i , p < 0.01, N = 10). Above results obtained from in vivo studies in both human and mouse, together with our most recently findings that XIAP is overexpressed in BBN‐induced mouse bladder cancers, leads us to investigate the potential association of XIAP overexpression with RhoGDIβ abundance.…”

“…Nevertheless, the overall role of XIAP in cancer progression might be dependent on cancer tissues and cell types. Our most recent studies reveal that XIAP and its RING domain was crucial for human BC invasion in vitro cell culture model and invasive bladder cancer development in mice exposed to N ‐butyl‐ N ‐(4‐hydroxybutyl) nitrosamine (BBN) in drinking water in vivo animal model . Thus, the discovery of XIAP downstream effectors and evaluation of the mechanisms underlying XIAP and its RING domain modulation of human BC invasion and metastasis is of tremendous importance for understanding nature of the BC invasion and metastasis.…”

ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis

“…These cells were maintained in DMEM-F12 (1:1) (Invitrogen) supplemented with 5% heat-inactivated fetal bovine serum (FBS), 2 μM L-glutamine, and 25 μg/mL gentamycin. The human normal bladder urothelial cell line UROtsa was a gift from Dr. Scott Garrett (Department of Pathology, School of Medicine and Health Sciences, University of North Dakota) 53 and was used in our previous publication 54 . These cells were maintained at 37°C in a 5% CO 2 incubator with RPMI 1640 medium supplemented with 10% FBS (26140079) and 2 mM L-glutamine (25030164).…”

XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell

“…Our recent studies have revealed several non-apoptosis-related functions of XIAP via its RING domain, including the upregulation of cyclin D1, while promoting bladder cancer cell growth [18], and the promotion of F-actin formation and colon cancer cell invasion via inhibition of SUMOlation of RhoGDIα (Rho GDP-dissociation inhibitor α) at lys-138 [53]. Our most recent studies also reveal that the RING domain of XIAP promotes Sp1-mediated transcription of miR-4295, which targets the 3′ UTR of p63α mRNA, for inhibiting p63α translation and enhancing urothelial transformation [54]. In the dissection of BIR domain functions, we find that BIR domains can directly bind to E2F1 (E2F transcription factor 1) and increase its transactivation and cyclin E expression [21].…”