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Abstract
Although the precursor protein of NFκB2 (p100) is thought to act as a tumor suppressor in mammalian cells, the molecular mechanism of its anti-tumor activity is far from clear. Here, we are, for the first time, to report that p100 protein expression was dramatically decreased in bladder cancers of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-treated mice and human patients. Knockdown of p100 in cultured human bladder cancer cells promoted anchorage-independent growth accompanied with elevating abundance of cell-cycle-related proteins and accelerated cell-cycle progression. Above effects could be completely reversed by ectopically expression of p100, but not p52. Mechanistically, p100 inhibited Cyclin D1 protein translation by activating the transcription of LARP7 and its hosted miR-302d, which could directly bind to 3′-UTR of cyclin d1 mRNA and inhibited its protein translation. Furthermore, p100 suppressed the expression of PHLPP2 (PH domain and leucine-rich repeat protein phosphatases 2), thus promoting CREB phosphorylation at Ser133 and subsequently leading to miR-302d transcription. Taken together, our studies not only for the first time establish p100 as a key tumor suppressor of bladder cancer growth, but also identify a novel molecular cascade of PHLPP2/CREB/miR-302d that mediates the tumor suppressive function of p100.
Highlights
Mammalian nuclear factor κB (NFκB) consists of five members, including RelA/p65, c-Rel, RelB, NFκB1(p50) and NFκB2(p52)
Knockdown of PHLPP2 showed remarkable activation of cAMP response element-binding protein (CREB) phosphorylation at Ser133 and miR302d expression with profound inhibition of Cyclin D1 protein expression in both p100−/− and UMUC3(shp100) cells (Figure 7C–7E). These results demonstrate that PHLPP2 is a p100 downstream phosphatase being mediation of CREB phosphorylation at Ser133, by which activates miR-302d transcription, and in turn targeting cyclin d1 mRNA 3′-UTR and inhibiting Cyclin D1 protein translation
Tumor suppressive function of p100 is thought to be associated with its inhibitory role in NFκB activation [34, 35], its expression and association with bladder cancer have never been explored in any previous studies
Summary
Mammalian nuclear factor κB (NFκB) consists of five members, including RelA/p65, c-Rel, RelB, NFκB1(p50) and NFκB2(p52). The diverse tumor-promoting roles of NFκB in cancer cell proliferation, anti-apoptosis, angiogenesis, invasion and metastasis, are well established [3,4,5,6,7,8,9], much less is known about how p100, a precursor protein of NFκB2, acts as a tumor suppressor in many mammalian cells [10]. We assessed the relative abundance of p100 between human BC tissues and their adjacent normal tissues, and between invasive mouse BC tissues and normal mouse bladder tissues; examined the role of p100 in suppression of anchorage-independent BC cell growth using loss- and www.impactjournals.com/oncotarget gain-expression experimental systems, and explored the molecular mechanisms of p100 suppression of urothelial proliferation and tumorigenesis. We discovered that p100 inhibited Cyclin D1 protein translation via suppression of PH domain and leucine-rich repeat protein phosphatases 2 (PHLPP2) expression, thereby leading to activation of CREB/miR-302d axis
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