Aberrant Hippo-YAP/TEAD Signaling Drives Malignant Transcriptional Reprogramming in External Auditory Canal Squamous...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• External auditory canal squamous cell carcinoma (EACSCC) is a rare cancer with poorly understood molecular mechanisms.
• Current therapeutic strategies for EACSCC are limited due to a lack of evidence-based approaches.

Purpose of the Study:

• To investigate the molecular underpinnings of EACSCC using integrated multi-omics analyses.
• To identify potential therapeutic targets for EACSCC.

Main Methods:

• Integrated RNA sequencing (RNA-seq) and ChIP sequencing (ChIP-seq) for YAP and H3K27Ac in EACSCC and normal ear skin.
• In vitro and in vivo functional experiments using small molecule TEAD inhibitors (smTEADi) and gene knockdown/overexpression.
• Analysis of YAP and PITX2 co-expression in patient tissues.

Main Results:

• RNA-seq identified hyperactivation of the YAP/TEAD transcriptional program in EACSCC, correlating with poor outcomes.
• ChIP-seq revealed increased TF binding site accessibility and EACSCC-specific super enhancers (SEs), with YAP-bound SEs linked to EGFR signaling.
• smTEADi VT104 suppressed EACSCC cell proliferation and clonogenicity, inducing YAP-PITX2 binding. PITX2 knockdown enhanced VT104 sensitivity, while overexpression promoted tumor growth.
• Nuclear YAP and PITX2 co-expression in EACSCC tissues correlated with poor prognosis.

Conclusions:

• The YAP-driven transcriptional program is hyperactivated in EACSCC and represents a potential therapeutic target.
• Targeting YAP/TEAD signaling, potentially in conjunction with modulating PITX2, offers a promising therapeutic strategy for EACSCC.