2. Academic Validation
  3. WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

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.
Xiaomeng Gao 1,  Jieqiong You 1,  Yanling Gong 1,  Meng Yuan 1 2,  Haiying Zhu 1,  Liang Fang 3,  Hong Zhu 1 4,  Meidan Ying 1 4,  Qiaojun He 1 2 4,  Bo Yang 1 2,  Ji Cao 1 2 4
Affiliations

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.
PMID: 35530152 DOI: 10.1016/j.apsb.2021.10.021
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.

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