LAUSR

Sorafenib resistance is a major challenge in the therapy for advanced hepatocellular carcinoma (HCC)1 . However, the underlying molecular mechanism of HCC resistance to sorafenib remains unclear. Activator of thyroid and retinoid receptor (ACTR, also known as SRC-3), overexpressed in HCC patients, plays an important oncogenic role in HCC, however, the link between ACTR and sorafenib resistance in HCC is unknown. Our study demonstrated that in sorafenib-resistant HCC xenografts, ACTR was one of the most upregulated genes. ACTR increases sorafenib resistance via regulation of Warburg effect. ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, extracellular acidification rate (ECAR), and reduction of oxygen consumption rate (OCR). Crucially, glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and vivo. Mechanistically, ACTR knockout or knockdown decreases the expression of glycolytic enzymes. In HCC patients, ACTR expression is positively correlated with glycolytic gene expression and predicts the poorer outcome. Furthermore, ACTR interacts with the central regulator of the Warburg effect, c-Myc, and promotes its recruitment to glycolytic gene promoters. Our findings provide new clues regarding the role of ACTR as a prospective sensitizing target for sorafenib therapy in HCC.