Circular RNA circATM binds PARP1 to suppress Wnt/β-catenin signaling and induce cell cycle arrest in gastric cancer cells

Abstract

Introduction: Gastric cancer (GC) is a common malignancy, which is associated with high rates of morbidity and mortality. Despite therapeutic advancements, there is an overall lack of effective treatment options for patients with GC, particularly those with advanced and metastatic disease. The roles of circular (circ)RNAs in tumorigenesis are being increasingly recognized, among which circRNAs are defined as miRNA/protein sponges, scaffolds, or protein coding templates.

Objectives: The aim of the present study is to investigate the functions of circATM in GC and elucidate the underlying molecular mechanism.

Methods: By circRNA sequencing in GC tissues, we identified a novel 526 nt circRNA, circATM, generating from exons 3-6 of the ATM gene. Through circRNA pull-down and RNA immunoprecipitation assays, we identified PARP1 as one of circATM binding proteins. The EdU, colony formation, wound healing, dual-luciferase reporter, cell cycle assays were employed to evaluated circATM functions in vitro. The GC xenograft model was used to determine the role of circATM in vivo.

Results: Knocking down circATM promoted GC cells growth in vivo and in vitro. Meanwhile, the overexpression of circATM increased the levels of p16, p21, and p27, and decreased those of β-catenin and c-Myc. Furthermore, we identified PARP1 as a circATM-interacting partner. Mechanistically, circATM bound to the zinc finger motif of Ⅱ-Ⅲ domains of PARP1 to block its recruitment to sites of DNA damage, triggering cell cycle arrest and sequestering β-catenin from the PARP1/β-catenin/TCF4 complex, leading to the suppression of Wnt/β-catenin signaling. Additionally, circATM facilitated the ubiquitin-proteasome degradation of PARP1, further jeopardizing its ability to mediate DNA damage repair.

Conclusion: Taken together, we defined circATM as a novel gastric tumor suppressor via interacting with PARP1, which indicate that circATM may be a promising biomarker for the diagnosis and therapy of GC.

Keywords: Cell cycle; Gastric cancer; PARP1; circATM; β-catenin.