STAT3-mediated transactivation of NOVA2 promotes lung adenocarcinoma metastasis by splicing SMAD4.

Metastasis remains the primary cause of mortality in lung adenocarcinoma (LUAD) patients. However, the molecular mechanisms underlying LUAD cell metastasis are only partially elucidated. Here, by performing integrated bioinformatic analysis of clinical data, RNA-binding protein (RBP) NOVA2 is identified as a pivotal LUAD metastasis-associated regulator. NOVA2 expression is elevated in metastatic LUAD tissues and correlates with poor prognosis of LUAD patients. Functionally, NOVA2 depletion suppresses epithelial-mesenchymal transition (EMT), migration, and invasion in vitro, and attenuates LUAD cell metastasis in vivo. Mechanistically, histone acetyltransferase p300 augments H3K27 acetylation level and facilitates the binding of STAT3 to the NOVA2 promoter, which in turn promotes NOVA2 transcription. Increased NOVA2 expression induces exon skipping (exons 6-7) in SMAD4 to generate a truncated splicing isoform (termed Δ-SMAD4). The resulting Δ-SMAD4 isoform evades E3 ubiquitin ligase β-TrCP-mediated ubiquitination, maintaining its ability to form complex with SMAD3 (R-SMAD) and sustain TGF-β/SMAD signaling. Moreover, in NOVA2-overexpressing LUAD cells, Δ-SMAD4 knockdown has stronger inhibitory effects on TGF-β-induced EMT and invasion than does SMAD4 knockdown. In summary, our findings identify a novel mechanism by which STAT3-mediated transcriptional upregulation of NOVA2 promotes SMAD4 splicing in metastatic LUAD, and suggest that the STAT3-NOVA2-Δ-SMAD4 axis drives EMT and LUAD metastasis, which may be a promising therapeutic target for treating LUAD.