LAUSR

ABSTRACT Transcription factor E26 transformation specific sequence 1 (ETS‐1) is a primary regulator in the metastasis of human cancer cells, especially hepatocellular carcinoma (HCC) cells; and it would affect the prognosis of HCC patients who received chemotherapies. However, the regulatory role of ETS‐1 in the resistance of HCC cells to molecular‐targeting agent remains poorly understood. In the present work, we demonstrate that high ETS‐1 expression correlates with poor prognosis of advanced HCC patients received Sorafenib treatment. Mechanistically, ETS‐1 binds to nuclear Pregnane X receptor (PXR) directly and enhances PXR’s transcription factor activity, which further leads to the induction of the PXR’s downstream multi‐drug resistance related genes. Overexpression of ETS‐1 accelerates the metabolic clearance of Sorafenib in HCC cells and leads to the better survival and faster migration of those cells. The therapeutic studies show that ETS‐1 promotes the Sorafenib‐resistance of HCC tumor models and ETS‐1 blockade enhances the anti‐tumor capacity of Sorafenib by decreasing PXR activation. Thus, our study suggests that ETS‐1 could enhance the activation of PXR and be a potential therapeutic target for overcoming Sorafenib resistance in HCC treatment.