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

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. A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. .

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References
1.
Guttridge D, Mayo M, Madrid L, Wang C, Baldwin Jr A . NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science. 2000; 289(5488):2363-6. DOI: 10.1126/science.289.5488.2363. View

2.
Ohtsu N, Nakatani Y, Yamashita D, Ohue S, Ohnishi T, Kondo T . Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway. Cancer Res. 2015; 76(1):171-81. DOI: 10.1158/0008-5472.CAN-15-0884. View

3.
Reynaud E, Leibovitch M, Tintignac L, Pelpel K, Guillier M, Leibovitch S . Stabilization of MyoD by direct binding to p57(Kip2). J Biol Chem. 2000; 275(25):18767-76. DOI: 10.1074/jbc.M907412199. View

4.
Ballinger M, Goode D, Ray-Coquard I, James P, Mitchell G, Niedermayr E . Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol. 2016; 17(9):1261-71. DOI: 10.1016/S1470-2045(16)30147-4. View

5.
Perez-Rosado A, Artiga M, Vargiu P, Sanchez-Aguilera A, Alvarez-Barrientos A, Piris M . BCL6 represses NFkappaB activity in diffuse large B-cell lymphomas. J Pathol. 2008; 214(4):498-507. DOI: 10.1002/path.2279. View