TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

Abstract

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 m 6 A 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.

High TEAD4 Expression is Associated With Aggressive Clear Cell Renal Cell Carcinoma, Regardless of YAP1 Expression

“…Liu et al 18 suggested that TEAD4 plays a significant role in tumor progression and metastasis in colorectal cancer, independently of YAP. Transcriptional activity of TEAD4, independent of YAP or transcriptional coactivator with PDZ-binding motif, was also observed in nasopharyngeal cancers 38 . In this study, YAP1-low/TEAD4-high expression was significantly associated with aggressive clinicopathologic variables in CCRCC.…”

“…Transcriptional activity of TEAD4, independent of YAP or transcriptional coactivator with PDZ-binding motif, was also observed in nasopharyngeal cancers. 38 In this study, YAP1-low/ TEAD4-high expression was significantly associated with aggressive clinicopathologic variables in CCRCC. Regardless of the YAP1 expression status, CCRCC with high TEAD4 expression was associated with worse OS and DFS, implying that high TEAD4 expression plays a critical role in determining survival.…”

Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential

“…Additionally, some studies have demonstrated that VP is proteotoxic and lacks specificity, 160 which limits its application in the clinic. Nevertheless, inhibitors of YAP–TEAD/TEAD, including MYF‐01‐37, 161 VGLL4 peptide mimics, 23 peptide 17, 162 and MGH‐CP1, are still being explored 163 . Unlike others in the group, MYF‐01‐37 has since been identified as a covalent binding agent for TEAD, which effectively targets NSCLC cells with EGFR mutations 161 .…”

“…Regarding the mechanism, VGLL4 peptide mimetics compete with YAP binding to TEAD via the TDU domain, thus functioning as a YAP antagonist 23 . The MGH‐CP1, an inhibitor of auto‐palmitoylation of TEAD2 and TEAD4, inhibits nasopharyngeal carcinoma cell migration, invasion, and cisplatin resistance 163 . In addition, work by Pobbati et al 164 .…”

“…23 The MGH-CP1, an inhibitor of auto-palmitoylation of TEAD2 and TEAD4, inhibits nasopharyngeal carcinoma cell migration, invasion, and cisplatin resistance. 163 In addition, work by Pobbati et al 164 found that a nonsteroidal anti-inflammatory drug (NSAID), flufenamic acid, inhibits TEAD function and TEAD-YAP-dependent processes by binding to the deep hydrophobic pocket of TEAD. These studies provide a theoretical basis for the idea that TEAD transcription factors can be targeted by small-molecule drugs.…”