Wogonin potentiates the irradiation effect on hepatocellular carcinoma by activating the Hippo-Yes-associated protein/transcriptional co-activator with PDZ-binding motif pathway

OBJECTIVE: To investigate whether wogonin increases the radiosensitivity of hepatocellular carcinoma (HCC) cells by activating Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling. METHODS: HCC cells were treated with irradiation and wogonin; their proliferation and apoptosis were evaluated. Xenograft models were established to assess the radio-synergistic effects of wogonin; we evaluated whether wogonin influences the efficacy of radiotherapy in HCC cells by activating Hippo-YAP/TAZ signaling. RESULTS: Fifty micromolar wogonin enhanced the radiosensitivity of HCC cells; 4-Gy X-rays promoted apoptosis in HCC cells. Wogonin pretreatment significantly increased radiosensitivity. In xenograft models, tumor weight and volume in the 100 mg/kg wogonin plus irradiation group were significantly reduced; pYAP and pTAZ levels were downregulated in HCC cells treated with radiotherapy. Following treatment with 4-Gy X-rays and 100 μM wogonin, the relative pYAP/total YAP and pTAZ/total TAZ ratios increased. We identified the possible target genes of YAP/TAZ: AXL, CCN1, and CCN2. WB results revealed the upregulation of AXL, CCN1, and CCN2 in the irradiation group. However, in the group receiving irradiation and wogonin, the protein expression levels of AXL, CCN1, and CCN2 were downregulated. XMU-MP-1 inhibited pYAP and pTAZ expression in the combination treatment group, thereby promoting AXL, CCN1, and CCN2 expression. The proliferative ability of HCC cells in the wogonin plus irradiation group was partially recovered following treatment with XMU-MP-1. Apoptosis in HCC cells was reversed after pretreatment with 2 μM XMU-MP-1 in the wogonin plus irradiation group. CONCLUSION: Wogonin may modulate Hippo-YAP/TAZ signaling and enhance the radiosensitivity of HCCs.