YAP1-mediated suppression of USP31 enhances NFkB activity to promote sarcomagenesis
PublisherAmerican Association for Cancer Research Inc.
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AbstractTo 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 NFkB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFkB 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, NFkB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Copyright 2018 American Association for Cancer Research.
SponsorsThis work was funded by The University of Pennsylvania Abramson Cancer Center (to T.S.K. Eisinger-Mathason), The Penn Sarcoma Program Center (to T.S.K. Eisinger-Mathason), Steps to Cure Sarcoma Center (to T.S.K. Eisinger-Matha-son), and NIH/NCI P50 CA100707 (to J. Qi).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85047860006&doi=10.1158%2f0008-5472.CAN-17-4052&partnerID=40&md5=002f85cd84b865279fc496a871346ad4; http://hdl.handle.net/10713/9723