Inorganic Arsenic-Induced Up-Regulation of MALAT1 Affects Cell Apoptosis via Disrupting the Binding Between IKBα and IKKβ, P65

Abstract

The toxicity and carcinogenicity of the environmental pollutant arsenic have been widely recognized. Dysregulation of apoptosis and proliferation, mediated by specific genes or signaling pathways, plays a pivotal role in arsenic-induced carcinogenesis. LncRNA MALAT1 is an adverse prognostic marker in lung adenocarcinoma patients and is associated with metastasis. Here, we investigated the arsenic-induced upregulation of MALAT1 and its impact on apoptosis. Our study combined epidemiological analyses of arsenic exposure with in vitro experiments. qRT-PCR assessed gene expression, while CCK-8, JC-1 staining, Hoechst 33342/PI assays, and Western blot analysis evaluated apoptosis, mitochondrial membrane potential, and apoptotic markers. RNA immunoprecipitation (RIP) and co-immunoprecipitation (Co-IP) assays elucidated interactions between MALAT1 and key proteins. Our findings revealed that inorganic arsenic upregulates MALAT1 expression in vivo and in vitro. We show that low expression of MALAT1 diminishes survival and facilitates apoptosis in 16HBE cells, and knockdown of MALAT1 inhibits the mRNA transcription of NF-κB pathway-related genes BCL2, iap-1 and IκBα in 16HBE cells. Mechanistically, MALAT1 knockdown attenuated IKBα phosphorylation and ubiquitination, impairing NF-κB pathway activation. MALAT1 was proven to interact with IKBα, P65 and P50. Knockdown of MALAT1 reduces the binding of IKBα to IKKβ and lowers IκBα protein phosphorylation. Meanwhlie, low expression of MALAT1 enhances IKBα-P65 binding while weakening IKBα-IKKβ interactions, making it disadvantageous for IKBα to detach from the trimer formed by IKBα, P65 and P50. The repression of NF-κB signaling pathway target genes is responsible for cell apoptosis. Arsenic-promoted elevated expression of MALAT1 impinges cell proliferation and apoptosis, providing a scientific rationale for arsenic toxicity and carcinogenicity.