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Cancer Res. 2018 May 15;78(10):2705-2720. doi: 10.1158/0008-5472.CAN-17-4052. Epub 2018 Feb 28.

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

Author information

1
Abramson Family Cancer Research Institute, Department of Pathology & Laboratory Medicine, Penn Sarcoma Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Department of Orthopedic Surgery, Penn Sarcoma Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
4
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. karineis@pennmedicine.upenn.edu Jun_qi@dfci.harvard.edu.
6
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
7
Abramson Family Cancer Research Institute, Department of Pathology & Laboratory Medicine, Penn Sarcoma Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. karineis@pennmedicine.upenn.edu Jun_qi@dfci.harvard.edu.

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.

PMID:
29490948
PMCID:
PMC6314302
DOI:
10.1158/0008-5472.CAN-17-4052
[Indexed for MEDLINE]
Free PMC Article

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