TOPBP1 regulates resistance of gastric cancer to oxaliplatin by promoting transcription of PARP1

Abstract

Gastric cancer (GC) is the third leading cause of cancer-associated mortality worldwide. The platinum derivative oxaliplatin is widely applied in standard GC chemotherapy but recurrence and metastasis are common in advanced GC cases due to intrinsic or induced chemoresistance. Poly(ADP-Ribose) polymerase 1 (PARP1) is an enzyme crucial for repairing DNA damage induced by platinum compounds, which undermines the effectiveness of platinum-based chemotherapy. Data from the current study showed that topoisomerase IIβ binding protein 1 (TOPBP1), an interacting partner of topoisomerase IIβ, is highly expressed in oxaliplatin-resistant GC (OR-GC) cells and promotes PARP1 transcription through direct binding to its proximal promoter region. Furthermore, AKT-mediated phosphorylation of TOPBP1 at Ser1159 was indispensable for inducing PARP1 expression in OR-GC cells. Disruption of the TOPBP1/PARP1 regulatory pathway decreased cell viability and augmented apoptosis of OR-GC cells. The positive correlation between TOPBP1 and PARP1 was confirmed using both the TCGA database and immunohistochemical analysis of GC tissues. In GC patients receiving oxaliplatin treatment, high expression of TOPBP1 or PARP1 was associated with poor prognosis. Our finding that the TOPBP1/PARP1 pathway facilitates acquisition of oxaliplatin resistance uncovers a novel mechanism underlying platinum-based chemotherapy resistance in gastric cancer that may be utilized for developing effective therapeutic strategies.