In the present study, we showed that YAP nuclear localization was significantly increased in both hypoxic HCC cells and xenograft tumours, along with increased mRNA levels of the YAP target genes AREG, CTGF and Cyr61. Silencing of YAP with small interfering RNA (siRNA) sensitized the cells to sorafenib under hypoxia, thus highlighting the contribution of YAP to hypoxia-mediated sorafenib resistance. This evidence concerns the gene CCN2 and hepatocellular carcinoma.