WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit.
10.1016/j.apsb.2021.10.021
- Author:
Xiaomeng GAO
1
;
Jieqiong YOU
1
;
Yanling GONG
1
;
Meng YUAN
1
;
Haiying ZHU
1
;
Liang FANG
2
;
Hong ZHU
1
;
Meidan YING
1
;
Qiaojun HE
1
;
Bo YANG
1
;
Ji CAO
1
Author Information
1. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
2. Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.
- Publication Type:Journal Article
- Keywords:
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;
GSK3β, glycogen synthase kinase 3β;
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;
β-Catenin destruction complex
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1225-1239
- CountryChina
- Language:English
-
Abstract:
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 β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-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.
