期刊
MOLECULAR THERAPY
卷 29, 期 6, 页码 2134-2150出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2021.02.017
关键词
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资金
- National Natural Science Foundation of China [82072676]
- Shandong University Multidisciplinary Research and Innovation Team of Young Scholars [2020QNQT002]
- Shandong Province Major Research and Design Program [2018GSF118169]
- Natural Science Foundation of Shandong Province [ZR2019MH008]
- Jinan City Science and Technology Development Program [201805017, 201805013]
- Clinical Research Innovation Fund Project [CXPJJH118000012018240]
- Hengrui Hepatobiliary and Pancreatic Foundation [Y2017144]
This study demonstrates that WDR5 interacts with c-Myc in cholangiocarcinoma (CCA), leading to increased HIF-1 alpha expression and stability, thereby promoting tumor metastasis and invasion.
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 alpha (HIF-1 alpha) accumulation by binding with histone deacetylase 2 (HDAC2) and increasing histone 3 lysine 4 acetylation (H3K4ac) deacetylation of the prolyl hydroxylase domain protein2 (PHD2) promoter, resulting in the attenuation of chromatin opening and PHD2 expression, and eventually leading to HIF-1 alpha stabilization and accumulation. In conclusion, WDR5 facilitated EMT and metastasis of CCA by increasing HIF-1 alpha accumulation in a Myc-dependent pathway to promote HIF-1 alpha transcription and a Myc-independent pathway to stabilize HIF-1 alpha.
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