WSB1 regulates c-Myc expression through ß-catenin signaling and forms a feedforward circuit.
Acta Pharm Sin B
; 12(3): 1225-1239, 2022 Mar.
Article
em En
| MEDLINE
| ID: mdl-35530152
The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the ß-catenin pathway. Mechanistically, WSB1 affected ß-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor ß-TRCP recruitment, which inhibited the ubiquitination of ß-catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.
ATM, serine-protein kinase ATM; CHIP, chromatin immunoprecipitation; CK1, casein kinase 1; Cancer treatment; EBP2, probable rRNA-processing protein EBP2; ESC complex, elongin B/C-cullin 2/5-SOCS box containing ubiquitin ligase protein complex; Feedback loop; GSK3ß, glycogen synthase kinase 3ß; HCC, hepatocellular carcinoma; HIF1-α, hypoxia induced factor 1-alpha; IHC, immunohistochemistry; PLK1, serine/threonine-protein kinase PLK1; PP2A, serine/threonine protein phosphatase 2A; PROTAC, proteolysis targeting chimaera; RhoGDI2, Rho GDP dissociation inhibitor 2; TFs, transcription factors; Transcription factors; Tumorigenesis; Ubiquitination-proteasome pathway; WSB1; WSB1, WD repeat and SOCS box containing 1; c-Myc; c-Myc, proto-oncogene c-Myc; eIF4F, eukaryotic translation initiation factor 4F; ß-Catenin destruction complex
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Acta Pharm Sin B
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Holanda