PUBLICATION
FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling
- Authors
- Yang, Y., Zhang, Y., Cao, J., Su, Z., Li, F., Zhang, P., Zhang, B., Liu, R., Zhang, L., Xie, J., Li, J., Zhang, J., Chen, X., Hong, A.
- ID
- ZDB-PUB-230423-50
- Date
- 2023
- Source
- Journal of experimental & clinical cancer research : CR 42: 9696 (Journal)
- Registered Authors
- Keywords
- Combination therapy, EZH2, FGFR4, Hepatocellular carcinoma, Non-canonical NF-kB signaling, YAP signaling
- MeSH Terms
-
- Zebrafish Proteins
- Cell Proliferation
- Animals
- Zebrafish
- Carcinoma, Hepatocellular*/drug therapy
- Carcinoma, Hepatocellular*/genetics
- Carcinoma, Hepatocellular*/metabolism
- Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Enzyme Inhibitors/therapeutic use
- Liver Neoplasms*/drug therapy
- Liver Neoplasms*/genetics
- Liver Neoplasms*/metabolism
- Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors
- Enhancer of Zeste Homolog 2 Protein/metabolism
- Cell Line, Tumor
- Mice
- YAP-Signaling Proteins*/drug effects
- YAP-Signaling Proteins*/metabolism
- Apoptosis
- Humans
- PubMed
- 37085881 Full text @ J. Exp. Clin. Cancer Res.
Citation
Yang, Y., Zhang, Y., Cao, J., Su, Z., Li, F., Zhang, P., Zhang, B., Liu, R., Zhang, L., Xie, J., Li, J., Zhang, J., Chen, X., Hong, A. (2023) FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling. Journal of experimental & clinical cancer research : CR. 42:9696.
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, but current treatment options remain limited and cause serious life-threatening side effects. Aberrant FGFR4 signaling has been validated as an oncogenic driver of HCC, and EZH2, the catalytic subunit of the PRC2 complex, is a potential factor that contributes to acquired drug resistance in many tumors, including HCC. However, the functional relationship between these two carcinogenic factors, especially their significance for HCC treatment, remains unclear. In this study, we systematically evaluated the feasibility of a combination therapy targeting FGFR4 and EZH2 for HCC.
Methods RNA sequencing data of patients with Liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) were analyzed to determine FGFR4 and EZH2 expression and their interaction with prognosis. Moreover, the HCC cell lines, zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors were treated with FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for HCC both in vitro and in vivo. Furthermore, RNA-Seq was performed in combination with ChIP-Seq data analysis to investigate the critical mechanism underlying the combination treatment with Roblitinib and CPI-169.
Results EZH2 accumulated through the non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment, and the elevated EZH2 levels led to the antagonism of HCC against Roblitinib (FGFR4 inhibitor). Notably, knockdown of EZH2 sensitized HCC cells to Roblitinib, while the combination treatment of Roblitinib and CPI-169 (EZH2 inhibitor) synergistically induced the HCC cell apoptosis in vitro and suppressed the zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors development in vivo. Moreover, Roblitinib and CPI-169 synergistically inhibited HCC development via repressing YAP signaling.
Conclusions Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping