NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR‐145/Sp1/USP8‐dependent axis

Abstract

Although overexpression of the non‐canonical NFκB subunit p52 has been observed in several tumors, the function and mechanism of p52 in bladder cancer (BC) are less well understood. Here, we aimed at understanding the role and mechanism underlying p52 regulation of BC invasion. Human p52 was stably knockdown with shRNA targeting p52 in two bladder cancer cell lines (T24 and UMUC3). Two constitutively expressing constructs, p52 and p100, were stably transfected in to T24 or UMUC3, respectively. The stable transfectants were used to determine function and mechanisms responsible for p52 regulation of BC invasion. We demonstrate that p52 mediates human BC invasion. Knockdown of p52 impaired bladder cancer invasion by reduction of rhogdiβ mRNA stability and expression. Positively regulation of rhogdiβ mRNA stability was mediated by p52 promoting AUF1 protein degradation, consequently resulting in reduction of AUF1 binding to rhogdiβ mRNA. Further studies indicated that AUF1 protein degradation was mediated by upregulating USP8 transcription, which was modulated by its negative regulatory transcription factor Sp1. Moreover, we found that p52 upregulated miR‐145, which directly bound to the 3′‐UTR of sp1 mRNA, leading to downregulation of Sp1 protein translation. Our results reveal a comprehensive pathway that p52 acts as a positive regulator of BC invasion by initiating a novel miR‐145/Sp1/USP8/AUF1/RhoGDIβ axis. These findings provide insight into the understanding of p52 in the pathology of human BC invasion and progression, which may be useful information in the development of preventive and therapeutic approaches for using p52 as a potential target.

USP8 mitigates cognitive dysfunction of mice with sepsis‐associated encephalopathy

“…18 In addition, USP8 is capable of being modulated by transcription factors. 19 JASPAR database prediction showed that YY1 could bind to the USP8 promoter. After silencing YY1, the enrichment of YY1 in the USP8 promoter was decreased, along with the mRNA expression of USP8.…”

“…18 USP8 can be modulated by transcription factors. 19 Furthermore, the JASPAR database shows that YY1 can bind to the USP8 promoter. Nevertheless, the exact interaction between USP8 and YY1 and whether this interaction affects cognitive impairment after SAE remain unclear.…”

Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice

“…Some studies demonstrated that specific protein 1 (Sp1) decreased USP8 transcription. Huang et al revealed that inhibited sp1 expression by activating miR-145 [49]. In our future study, we need to address the molecular mechanism which H2S modulates USP8.…”

The Dual Function of RhoGDI2 in Immunity and Cancer

“…They have identified three different pathways—RhoGDI2/miR-200c/JNK2/Sp1/MMP2 pathway, XIAP/Erk/nucleolin/RhoGDI2 and, lastly, miR-145/Sp1/USP8/AUF1/RhoGDI2 pathway—through which they show that RhoGDI2 promotes BLCA invasion in vitro and lung metastasis in vivo. They observe that RhoGDI2 acts as a tumour and metastasis promoter, despite being widely demonstrated in the past as a metastasis suppressor, with no effect on the tumour [ 91 , 92 , 93 ]. Further investigations are required to better define the exact function of RhoGDI2 in BLCA.…”