WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

Xiaomeng Gao; Jieqiong You; Yanling Gong; Meng Yuan; Haiying Zhu; Liang Fang; Hong Zhu; Meidan Ying; Qiaojun He; Bo Yang; Ji Cao

doi:10.1016/j.apsb.2021.10.021

WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

Acta Pharm Sin B. 2022 Mar;12(3):1225-1239. doi: 10.1016/j.apsb.2021.10.021. Epub 2021 Oct 26.

Authors

Xiaomeng Gao¹, Jieqiong You¹, Yanling Gong¹, Meng Yuan^{1

2}, Haiying Zhu¹, Liang Fang³, Hong Zhu^{1

4}, Meidan Ying^{1

4}, Qiaojun He^{1

2

4}, Bo Yang^{1

2}, Ji Cao^{1

2

4}

Affiliations

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 The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China.
³ Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.
⁴ Cancer Center of Zhejiang University, Hangzhou 310058, China.

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.

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.