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

• Published in: Molecular therapy Vol. 29; no. 6; pp. 2134 - 2150
• Main Authors: Chen, Tianli, Li, Kangshuai, Liu, Zengli, Liu, Jialiang, Wang, Yue, Sun, Rongqi, Li, Zhipeng, Qiu, Bo, Zhang, Xiaoming, Ren, Guangli, Xu, Yunfei, Zhang, Zongli
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.06.2021; American Society of Gene & Cell Therapy
• Subjects: Acetylation; Animals; Biomarkers, Tumor; c-Myc; CCA; Cell Line, Tumor; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - mortality; Cholangiocarcinoma - pathology; Disease Models, Animal; EMT; Epithelial-Mesenchymal Transition - genetics; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Heterografts; HIF-1α; Histones; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Original; PHD2; Prognosis; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; WDR5; CCA; WDR5; HIF-1α; PHD2; c-Myc; EMT
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.02.017

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. [Display omitted] Chen et al. identified WDR5 as a prognostic biomarker of cholangiocarcinoma and depicted two distinct mechanisms of WDR5-enhanced HIF-1α accumulation: (1) WDR5 promoted HIF-1α mRNA synthesis via direct interaction with c-Myc, and (2) WDR5 inhibited HIF-1α protein hydroxylation and degradation by suppressing PHD2 expression, which relied on interacting with HDAC2 and deacetylizing H3K4ac.