LncRNA TMEM99 Complexes with IGF2BP2 to Inhibit Autophagy in Lung Adenocarcinoma

Abstract Lung adenocarcinoma (LUAD), the most common type of lung cancer, has a poor prognosis. Long noncoding RNAs (lncRNAs) play a key role in LUAD progression, yet the biological role of lncRNA TMEM99 remains unexplored. In this study, its function in inhibiting autophagy in LUAD is explored. Using RNA sequencing and quantitative reverse transcription PCR (qRT‐PCR), TMEM99 is found upregulated in LUAD tissues and cell lines, correlating with poor patient outcomes. In vivo and in vitro assays confirmed that TMEM99 promotes cell proliferation, migration, and invasion, and inhibits autophagy. Mechanistically, the 3′ end of TMEM99 binds to the K‑homology domain 1 (KH1) and KH4 domains of far upstream element‑binding protein 3 (FUBP3), stabilizing its protein. The TMEM99‐FUBP3 complex binds to p21 mRNA and recruits IGF2BP2 in an N⁶‑methyladenosine (m⁶A)‐dependent manner, which enhances mRNA stability and translation efficiency. This study reveals that TMEM99 plays a crucial regulatory role in LUAD autophagy and presents a novel cytoplasmic regulatory mechanism contributing to LUAD progression.