o8G-modified circKIAA1797 promotes lung cancer development by inhibiting cuproptosis.

Abstract

Background: Lung cancer is a serious threat to human life and health, but effective screening and treatment methods are lacking. Circular RNAs (circRNAs) have important biological functions and are closely related to tumour development. Some studies have shown that the 8-oxo-7,8-dihydroguanosine (o8G) modification plays a key role in the disease process, but the effect of the o8G modification on circRNAs has not been elucidated. Moreover, cuproptosis is a novel mode of cell death in which copper ions directly promote protein aggregation and the disruption of cellular metabolic pathways. The present study revealed that the o8G modification of circKIAA1797 occurs and promotes lung cancer development by inhibiting cuproptosis, which provides new perspectives for epitranscriptomic studies and the development of novel therapeutic approaches for lung cancer.

Methods: circRNA differential expression profiles in lung cancer were revealed via RNA high-throughput sequencing, and circKIAA1797 expression in lung cancer cell lines and tissues was detected using qPCR. Experiments such as o8G RNA immunoprecipitation (o8G RIP) and crosslinking immunoprecipitation (CLIP) were performed to explore the presence of o8G on circKIAA1797. The regulation of circKIAA1797 by the o8G reader Y-box binding protein 1 (YBX1) was explored using nuclear-cytoplasmic fractionation, actinomycin D (Act D) stability experiments and other experiments. circKIAA1797 silencing and overexpression systems were constructed for in vivo and in vitro experiments to study the role of circKIAA1797 in lung cancer development. Tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP), and immunofluorescence (IF) staining were subsequently conducted to reveal the molecular mechanism by which circKIAA1797 regulates cuproptosis and promotes lung cancer development.

Results: This study is the first to reveal the presence of o8G on circKIAA1797 and that YBX1 is a reader that recognises ROS-induced circKIAA1797 o8G modifications and increases the stability and cytoplasmic expression of circKIAA1797. circKIAA1797, which is associated with the tumour stage and prognosis, has been shown to significantly promote the biological function of lung cancer development both in vivo and in vitro. This study revealed that circKIAA1797 inhibits intracellular cuproptosis by binding to the ferredoxin 1 (FDX1) mRNA, decreasing FDX1 mRNA stability, inhibiting FDX1 expression, and binding to the signal transducer and activator of transcription 1 (STAT1) protein and inhibiting lipoyltransferase 1 (LIPT1) transcription; moreover, circKIAA1797 promotes the closure of the mitochondrial permeability transition pore (mPTP), inhibits cuproptosis, and ultimately promotes lung cancer development.

Conclusions: This study revealed the presence of the o8G modification in circKIAA1797, which plays an important role in the development of lung cancer. circKIAA1797 can inhibit cuproptosis by inhibiting key cuproptosis proteins and promoting mPTP closure, ultimately promoting the development of lung cancer. This study provides not only a new theoretical basis for an in-depth understanding of the molecular mechanisms of lung cancer development but also a potential target for lung cancer treatment.