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

Cancer Research
Shuai YeT S Karin Eisinger-Mathason

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 eff...Continue Reading

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Citations

May 28, 2019·Journal of Biomedical Science·Ming-Jer YoungJan-Jong Hung
Nov 6, 2018·Nature Communications·Yujie DengKinglun Kingston Mak
Apr 25, 2020·Cells·Heinrich KovarBranka Radic-Sarikas
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Dec 22, 2020·Immunology Letters·Paipai GuoQingtong Wang
May 4, 2020·Current Cancer Drug Targets·Xuemeng LeiZhihua Liu
Jun 30, 2021·Acta Biochimica Et Biophysica Sinica·Yaoyao HouXinpeng Chen
Jul 3, 2021·Cells·Sanda Iacobas, Dumitru A Iacobas

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