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.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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 10 Pg. 2705-2720 (05 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29490948 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• (+)-JQ1 compound
• Adaptor Proteins, Signal Transducing
• Amot protein, mouse
• Angiomotins
• Antineoplastic Agents
• Azepines
• Cell Cycle Proteins
• Intercellular Signaling Peptides and Proteins
• Microfilament Proteins
• NF-kappa B
• Phosphoproteins
• RNA, Small Interfering
• Transcription Factors
• Triazoles
• YAP-Signaling Proteins
• YAP1 protein, human
• Yap1 protein, mouse
• Vorinostat
• Protein Serine-Threonine Kinases
• USP31 protein, human
• Ubiquitin-Specific Proteases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Angiomotins
• Animals
• Antineoplastic Agents (pharmacology)
• Azepines (pharmacology)
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, pathology)
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Hippo Signaling Pathway
• Humans
• Intercellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Transgenic
• Microfilament Proteins (genetics)
• Muscle, Skeletal (pathology)
• NF-kappa B (metabolism)
• Phosphoproteins (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Sarcoma (genetics, pathology)
• Signal Transduction (genetics)
• Soft Tissue Neoplasms (genetics, pathology)
• Transcription Factors
• Triazoles (pharmacology)
• Ubiquitin-Specific Proteases (antagonists & inhibitors, biosynthesis)
• Vorinostat (pharmacology)
• YAP-Signaling Proteins