TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

Menée à l'aide de lignées cellulaires de carcinome rhinopharyngé, de modèles murins et d'échantillons tumoraux inclus en paraffine après prélèvement sur des patients, cette étude met en évidence le rôle du facteur de transcription TEAD4 dans le caractère agressif et la progression de la maladie

Résumé en anglais

The molecular basis underlying nasopharyngeal carcinoma (NPC) remains unclear. Recent progress in transcriptional regulatory network analysis helps identify the master regulator (MR) proteins that transcriptionally define malignant tumor phenotypes. Here, we investigated transcription factor-target interactions and identified TEA domain transcription factor 4 (TEAD4) as an MR of high-risk NPC. Precisely, TEAD4 promoted NPC migration, invasion and cisplatin resistance, depending on its autopalmitoylation. Mechanistically, YTHDF2 (YTH domain family 2) recognized WTAP (Wilms tumor 1–associating protein)–mediated TEAD4 m6A methylation to facilitate its stability and led to aberrant up-regulation of TEAD4. Up-regulated TEAD4 further drove NPC progression by transcriptionally activating BZW2 (basic leucine zipper and W2 domains 2) to induce the oncogenic AKT pathway. Moreover, the transcriptional activity of TEAD4 was independent of its canonical coactivators YAP/TAZ. Clinically, TEAD4 serves as an independent predictor of unfavorable prognosis and cisplatin response in NPC. Our data revealed the crucial role of TEAD4 in driving tumor malignancy, thus, may provide therapeutic vulnerability in NPC. TEAD4, a master regulator of high-risk NPC, drives NPC progression via BZW2 transcription activation to induce AKT pathway.