2. Academic Validation
  3. WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways

WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways

  • Mol Ther. 2021 Jun 2;29(6):2134-2150. doi: 10.1016/j.ymthe.2021.02.017.
Tianli Chen 1,  Kangshuai Li 1,  Zengli Liu 1,  Jialiang Liu 1,  Yue Wang 1,  Rongqi Sun 1,  Zhipeng Li 2,  Bo Qiu 1,  Xiaoming Zhang 3,  Guangli Ren 4,  Yunfei Xu 5,  Zongli Zhang 6
Affiliations

Affiliations

  • 1 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of General Surgery, Shandong Second Provincial General Hospital, Shandong Provincial ENT Hospital, Jinan, China.
  • 3 Department of General Surgery, Linyi People's Hospital, Linyi, China.
  • 4 Department of General Surgery, Shandong Provincial Third Hospital, Shandong University, Jinan, China.
  • 5 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: xuyunfei1988@126.com.
  • 6 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: zzlzzl1900@163.com.
PMID: 33601056 DOI: 10.1016/j.ymthe.2021.02.017
Abstract

Cholangiocarcinoma (CCA) is a highly aggressive malignancy with extremely poor prognoses. The oncogenic role and prognostic value of c-Myc in CCA is not well elucidated. WD repeat domain 5 (WDR5) is a critical regulatory factor directly interacting with c-Myc to regulate c-Myc recruitment at chromosomal locations, but the interaction of WDR5 and c-Myc in CCA was uncovered. In our study, we detected WDR5 and c-Myc expression in all CCA types, including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, and evaluated their prognostic significance. Consequently, we demonstrated that WDR5 was significantly correlated with poor prognosis of CCA and that WDR5 and c-Myc co-expression was a more sensitive prognostic factor. With in vitro and in vivo experiments and bioinformatics, we showed that WDR5 interacted with the Myc box IIIb (MBIIIb) motif of c-Myc and facilitated Myc-induced HIF1A transcription, thereby promoting the epithelial-mesenchymal transition (EMT), invasion, and metastasis of CCA. Moreover, WDR5 enhanced hypoxia-inducible factor 1 subunit α (HIF-1α) accumulation by binding with histone deacetylase 2 (HDAC2) and increasing histone 3 lysine 4 acetylation (H3K4ac) deacetylation of the prolyl hydroxylase domain protein 2 (PHD2) promoter, resulting in the attenuation of chromatin opening and PHD2 expression, and eventually leading to HIF-1α stabilization and accumulation. In conclusion, WDR5 facilitated EMT and metastasis of CCA by increasing HIF-1α accumulation in a Myc-dependent pathway to promote HIF-1α transcription and a Myc-independent pathway to stabilize HIF-1α.

Keywords

CCA; EMT; HIF-1α; PHD2; WDR5; c-Myc.

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