American Association for Cancer Research
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Figure S5 from YAP1-Mediated Suppression of USP31 Enhances NFκB Activity to Promote Sarcomagenesis

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posted on 2023-03-31, 02:01 authored by Shuai Ye, Matthew A. Lawlor, Adrian Rivera-Reyes, Shaun Egolf, Susan Chor, Koreana Pak, Gabrielle E. Ciotti, Avery C. Lee, Gloria E. Marino, Jennifer Shah, David Niedzwicki, Kristy Weber, Paul M.C. Park, Md. Zahidul Alam, Alison Grazioli, Malay Haldar, Mousheng Xu, Jennifer A. Perry, Jun Qi, T.S. Karin Eisinger-Mathason

The effects of SAHA/JQ1 on phospho-YAP1

Funding

University of Pennsylvania Abramson Cancer Center

Penn Sarcoma Program

Cure Sarcoma Center

NIH

NCI

History

ARTICLE ABSTRACT

To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFκB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFκB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment.Significance: A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Cancer Res; 78(10); 2705–20. ©2018 AACR.