Work

CircSP3 modulates apoptosis and participates in inorganic arsenic carcinogenesis through phosphorylation and ubiquitination of p65

Year: 2025

Type: article

Abstract: Inorganic arsenic (iAs) is a well-established carcinogen known to dysregulate gene expression, but its impact on circular RNAs (circRNAs) remains poorly characterized. Here, we demonstrated that NaAsO₂ (20, 40, 60 μmol/L) upregulated circSP3 (hsa_circ_0002642) expression in A549 cells (human lung adenocarcinoma cell line), independent of its methylated metabolites (MMA and DMA). Functionally, circSP3 silencing induced mitochondrial apoptosis, evidenced by reduced Bcl-2/Bax ratio, cytochrome c release, and caspase-7/PARP1 cleavage. Crucially, circSP3 knockdown attenuated NF-κB signaling through ubiquitin-mediated degradation of p65, concomitant with decreased phosphorylation of p65 (Ser536) and IκBα (Ser32/36). RNA immunoprecipitation revealed direct interactions between circSP3 and both p65 and IκBα, with iAs exposure reducing these binding affinities despite increasing circSP3 abundance. Collectively, our findings identify circSP3 as an iAs-responsive regulator of NF-κB-driven survival via post-translational control of p65 stability, providing mechanistic insights into iAs carcinogenesis. • There were significant differences in the effects of iAs and its main methylated metabolites (monomethylarsonic acid, MMA and DMA) on the expression of circSP3. • The low expression of circSP3 significantly inhibited the viability of A549 cells and markedly promoted cell apoptosis, which was related to the mitochondrial apoptotic pathway. • Silencing of circSP3 significantly inhibited the p65 signaling pathway, which was closely linked to the phosphorylation and ubiquitination of p65. • circSP3 interacted with both p65 and IκBα, while its low expression disrupted their binding.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.119055

Authors: Jinyao Yin, Qian Zhou, Chenglan Jiang, Shuting Li, Yuefeng He

Institutions: Harbin Medical University, Kunming Medical University, Chinese Center For Disease Control and Prevention, National Institute for Occupational Health and Poison Control

Language: English

Topic: Circular RNAs in diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,650