LncRNA NEAT1 Interacted With DNMT1 to Regulate Malignant Phenotype of Cancer Cell and Cytotoxic T Cell Infiltration via Epigenetic Inhibition of p53, cGAS, and STING in Lung Cancer

Abstract

Purpose: Lung cancer is the main cause of cancer-related mortality worldwide. We report here the biological role of nuclear paraspeckle assembly transcript 1 (NEAT1) in the pathogenesis of lung cancer and the underlying mechanisms. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis were used to evaluate expression of mRNA and protein. RNA immunoprecipitation (RIP) assay, chromatin immunoprecipitation followed by qPCR analysis, and reporter assay were used to detect DNA/RNA and protein binding. Tumorinfiltrating lymphocytes were assessed with hematoxylin-eosin staining. Cytotoxic T cell infiltration was evaluated with flow cytometric analysis and immunohistochemistry (IHC) staining. The changes of cell viability and cell invasive and migratory ability were analyzed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), colony formation, and Transwell assays, respectively. Syngeneic tumor model was set up to evaluate antitumor effect. Results: The results showed that NEAT1 was overexpressed in lung cancer tissues and cancer cell lines. This aberrant expression was closely related with tumor stage and lymph node metastasis. Tumor sample with high CD8 + showed lower NEAT1 expression. In vitro studies displayed that inhibition of NEAT1 with shRNA resulted in suppression of survival and migration/invasion of lung cancer cells. On the other side, NEAT1 was found to promote tumor growth via inhibiting cytotoxic T cell immunity in syngeneic models. Finally, NEAT1 was found to interact with DNMT1, which in turn inhibited P53 and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS/STING) expression. Conclusion: Our findings demonstrated that NEAT1 interacted with DNMT1 to regulate cytotoxic T cell infiltration in lung cancer via inhibition of cGAS/STING pathway. The results provided the novel mechanistic insight into the pathogenesis of lung cancer.

Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy

“…In another study, lncRNA NEAT1 was shown to facilitate the progression of gallbladder cancer via the upregulation of Survivin expression, suggesting its potential use as a biomarker in gallbladder cancer 34 . Multiple other studies show NEAT1 associations with osteoarthritis 35 , lung cancer 36 , and acute myeloid leukemia 37 . USP3-AS1 has also been reported as a potential biomarker for neuroblastoma pathogenesis studies 38 .…”

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

“…The activation of the STING signaling pathway in small cell lung cancer (SCLC) also enhances the protective effects of immunotherapy ( 157 ). Another study has indicated that the cGAS-STING signaling pathway inhibition due to upregulated nuclear paraspeckle assembly transcript 1 (NEAT1) in the lung cancer cells and tissues ( 158 ). NEAT1 interacts with DNA (cytosine-5)-methyltransferase 1 (DNMT1) to inhibit tumor suppressor p53 and cGAS-STING expression.…”

Function and Regulation of Nuclear DNA Sensors During Viral Infection and Tumorigenesis

“…Both HSV-1 infection and IFN-α treatment induce cGAS mRNA expression in neonatal PBMCs from 1-month-old infants ( 77 ). LncRNA NEAT1 epigenetically inhibits cGAS expression to regulate the malignant phenotype of cancer cells and cytotoxic T cell infiltration in lung cancer ( 78 ).…”