LAMTOR5-AS1 regulates chemotherapy-induced oxidative stress by controlling the expression level and transcriptional activity of NRF2 in osteosarcoma cells

• Published in: Cell death & disease 2021-12, Vol.12 (12), p.1125-1125, Article 1125
• Main Authors: Pu, Youguang, Tan, Yiao, Zang, Chunbao, Zhao, Fangfang, Cai, Cifeng, Kong, Lingsuo, Deng, Hui, Chao, Fengmei, Xia, Ran, Xie, Minghua, Ge, Fangfang, Pan, Yueyin, Cai, Shanbao, Huang, Dabing
• Format: Article
• Language: English
• Subjects: 13; 13/2; 38; 38/47; 631/67/1344; 631/80/82; 82; 82/51; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antibodies; Antioxidants; Biochemistry; Biomedical and Life Sciences; Bone cancer; Cell Biology; Cell Culture; Cell proliferation; Chemotherapy; Heme; Humans; Immunology; Life Sciences; Mice; Multidrug resistance; Next-generation sequencing; NF-E2-Related Factor 2 - metabolism; Non-coding RNA; Osteosarcoma; Osteosarcoma - genetics; Osteosarcoma - mortality; Osteosarcoma - pathology; Osteosarcoma cells; Oxidative Stress; Oxygenase; Sarcoma; Sequence analysis; Signal Transduction; Survival Analysis; Transcription; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04413-0

Long-noncoding RNAs (lncRNAs) play roles in regulating cellular functions. High-throughput sequencing analysis identified a new lncRNA, termed LAMTOR5-AS1, the expression of which was much higher in the chemosensitive osteosarcoma (OS) cell line G-292 than in the chemoresistant cell line SJSA-1. Further investigations revealed that LAMTOR5-AS1 significantly inhibits the proliferation and multidrug resistance of OS cells. In vitro assays demonstrated that LAMTOR5-AS1 mediates the interaction between nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2) and kelch-like ECH-associated protein 1 (KEAP1), which regulate the oxidative stress. Further mechanistic studies revealed that LAMTOR5-AS1 inhibited the ubiquitination degradation pathway of NRF2, resulting in a higher level of NRF2 but a loss of NRF2 transcriptional activity. High level of NRF2 in return upregulated the downstream gene heme oxygenase 1 (HO-1). Moreover, NRF2 controls its own activity by promoting LAMTOR5-AS1 expression, whereas the feedback regulation is weakened in drug-resistant cells due to high antioxidant activity. Overall, we propose that LAMTOR5-AS1 globally regulates chemotherapy-induced cellular oxidative stress by controlling the expression and activity of NRF2.