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The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer.
- Source :
-
Oncogene [Oncogene] 2020 Apr; Vol. 39 (17), pp. 3588-3603. Date of Electronic Publication: 2020 Mar 03. - Publication Year :
- 2020
-
Abstract
- CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.
- Subjects :
- Animals
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases genetics
Cullin Proteins genetics
Epigenesis, Genetic
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs genetics
Neoplasm Metastasis
Proto-Oncogene Proteins c-akt genetics
RNA, Neoplasm genetics
Urinary Bladder Neoplasms genetics
Urinary Bladder Neoplasms pathology
Class I Phosphatidylinositol 3-Kinases metabolism
Cullin Proteins metabolism
MicroRNAs metabolism
Proto-Oncogene Proteins c-akt metabolism
RNA, Neoplasm metabolism
Signal Transduction
Urinary Bladder Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 39
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 32127645
- Full Text :
- https://doi.org/10.1038/s41388-020-1236-1