YAP1-Mediated Suppression of USP31 Enhances NFκB Activity to Promote Sarcomagenesis

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Most adult soft tissue sarcomas lack identified oncogenic drivers, limiting targeted therapy effectiveness.
• Undifferentiated pleomorphic sarcoma (UPS) exhibits Hippo pathway deregulation and YAP1 stabilization, promoting proliferation and tumorigenesis.
• The precise mechanisms driving YAP1 dysregulation in UPS remain unclear.

Purpose of the Study:

• To investigate alternative mechanisms of sarcomagenesis in UPS.
• To identify potential therapeutic targets by understanding YAP1 deregulation.
• To explore the role of epigenetic modifications in UPS development.

Main Methods:

• Utilized autochthonous mouse models of UPS.
• Performed whole genome analyses to identify genetic and epigenetic alterations.
• Employed epigenetic modulators (vorinostat, JQ1) to assess therapeutic potential.
• Investigated the regulatory relationship between YAP1, AMOT, USP31, and NFκB signaling.

Main Results:

• Identified epigenetic silencing of angiomotin (AMOT) as a cause of constitutive YAP1 activity in some sarcomas.
• Demonstrated that epigenetic modulators restored AMOT expression and Hippo pathway signaling, inhibiting sarcomagenesis.
• Found that YAP1 promotes tumorigenesis by suppressing ubiquitin-specific peptidase 31 (USP31), a negative regulator of NFκB.
• Showed that combined epigenetic therapy restored USP31 expression and decreased NFκB activity.

Conclusions:

• Epigenetic silencing of AMOT is a key mechanism driving UPS via YAP1 stabilization.
• Restoring AMOT expression with epigenetic drugs can inhibit sarcoma growth and induce muscle differentiation.
• YAP1-mediated suppression of USP31 contributes to sarcomagenesis by enhancing NFκB signaling.
• Epigenetic reprogramming offers a promising therapeutic strategy for soft tissue sarcomas by targeting the Hippo pathway and NFκB signaling.