TY  - JOUR
AU  - Szulzewsky, Frank
AU  - Arora, Sonali
AU  - Hoellerbauer, Pia
AU  - King, Claire
AU  - Nathan, Erica
AU  - Chan, Marina
AU  - Cimino, Patrick J
AU  - Ozawa, Tatsuya
AU  - Kawauchi, Daisuke
AU  - Pajtler, Kristian W
AU  - Gilbertson, Richard J
AU  - Paddison, Patrick J
AU  - Vasioukhin, Valeri
AU  - Gujral, Taranjit S
AU  - Holland, Eric C
TI  - Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis.
JO  - Genes & development
VL  - 34
IS  - 15-16
SN  - 1549-5477
CY  - Cold Spring Harbor, NY
PB  - Laboratory Press
M1  - DKFZ-2020-01449
SP  -  1051-1064
PY  - 2020
N1  - Volume 34, Issue 15-16, 1 August 2020, Pages 1051-1064
AB  - YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.
LB  - PUB:(DE-HGF)16
C6  - pmid:32675324
DO  - DOI:10.1101/gad.338681.120
UR  - https://inrepo02.dkfz.de/record/157169
ER  -