Title: NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR-145/Sp1/USP8-dependent axis.
Authors: Xu, Jiawei; Hua, Xiaohui; Jin, Honglei; Zhu, Junlan; Li, Yang; Li, Jingxia; Huang, Chuangshu
Published In Mol Carcinog, (2019 05)
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.
PubMed ID: 30604907
MeSH Terms: Endopeptidases/genetics; Endopeptidases/metabolism*; Endosomal Sorting Complexes Required for Transport/genetics; Endosomal Sorting Complexes Required for Transport/metabolism*; Gene Expression Regulation, Neoplastic; Heterogeneous Nuclear Ribonucleoprotein D0; Heterogeneous-Nuclear Ribonucleoprotein D/genetics; Heterogeneous-Nuclear Ribonucleoprotein D/metabolism*; Humans; MicroRNAs/genetics; MicroRNAs/metabolism*; NF-kappa B p52 Subunit/genetics; NF-kappa B p52 Subunit/metabolism*; Protein Biosynthesis; Proteolysis; RNA Stability*; Sp1 Transcription Factor/genetics; Sp1 Transcription Factor/metabolism*; Tumor Cells, Cultured; Ubiquitin Thiolesterase/genetics; Ubiquitin Thiolesterase/metabolism*; Urinary Bladder Neoplasms/genetics; Urinary Bladder Neoplasms/metabolism; Urinary Bladder Neoplasms/pathology*; rho Guanine Nucleotide Dissociation Inhibitor beta/chemistry; rho Guanine Nucleotide Dissociation Inhibitor beta/genetics; rho Guanine Nucleotide Dissociation Inhibitor beta/metabolism*