A comprehensive evaluation of Hippo pathway silencing in sarcomas

Nicole M Merritt; Colleen A Fullenkamp; Sarah L Hall; Qining Qian; Chandni Desai; Jon Thomason; Allyn M Lambertz; Adam J Dupuy; Benjamin Darbro; Munir R Tanas

doi:10.18632/oncotarget.25824

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A comprehensive evaluation of Hippo pathway silencing in sarcomas

Journal article

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A comprehensive evaluation of Hippo pathway silencing in sarcomas

Nicole M Merritt, Colleen A Fullenkamp, Sarah L Hall, Qining Qian, Chandni Desai, Jon Thomason, Allyn M Lambertz, Adam J Dupuy, Benjamin Darbro and Munir R Tanas

Oncotarget, Vol.9(60), pp.31620-31636

08/01/2018

DOI: 10.18632/oncotarget.25824

PMCID: PMC6114978

PMID: 30167083

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Abstract

TAZ and YAP are transcriptional coactivators negatively regulated by the Hippo pathway that have emerged as key oncoproteins in several cancers including sarcomas. We hypothesized that loss of expression of the Hippo kinases might be a mechanism of activating TAZ and YAP. By immunohistochemistry, TAZ/YAP activated clinical sarcoma samples demonstrated loss of MST1 (47%), MST2 (26%), LATS1 (19%), and LATS2 (27%). Western blot similarly demonstrated loss of MST1 (58%), MST2 (25%), and LATS2 (17%). Treatment with MG132 demonstrated an accumulation of MST2 in 25% of sarcoma cell lines, indicating that proteosomal degradation regulates MST2 expression. qRT-PCR in sarcoma cell lines demonstrated loss of expression of the Hippo kinases at the RNA level, most pronounced in MST1 (42%) and MST2 (25%). 5-azacytidine treatment in sarcoma cell lines modestly reversed expression of predominantly MST1 (8%) and MST2 (17%), indicating CpG island hypermethylation can silence expression of MST1 and MST2 . Trichostatin A treatment reversed expression of MST1 (58%) and MST2 (67%), indicating histone deacetylation also plays a role in silencing expression of MST1 and MST2 . Loss of expression of the Hippo kinases is frequent in sarcomas and is due to a variety of mechanisms including regulation at the post-translational level and epigenetic silencing.

YAP

Research Paper

Hippo pathway

sarcoma

TAZ

epigenetics

Details

Title: Subtitle: A comprehensive evaluation of Hippo pathway silencing in sarcomas
Creators: Nicole M Merritt - Department of Pathology, University of Iowa, Iowa City, IA, USA
Colleen A Fullenkamp - Department of Pathology, University of Iowa, Iowa City, IA, USA
Sarah L Hall - Department of Pathology, University of Iowa, Iowa City, IA, USA
Qining Qian - Department of Pediatrics, University of Iowa, Iowa City, IA, USA
Chandni Desai - Department of Pathology, University of Iowa, Iowa City, IA, USA
Jon Thomason - Department of Pathology, University of Iowa, Iowa City, IA, USA
Allyn M Lambertz - Department of Pathology, University of Iowa, Iowa City, IA, USA
Adam J Dupuy - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
Benjamin Darbro - Department of Pediatrics, University of Iowa, Iowa City, IA, USA
Munir R Tanas - Department of Pathology, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.9(60), pp.31620-31636
DOI: 10.18632/oncotarget.25824
PMID: 30167083
PMCID: PMC6114978
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: Impact Journals LLC
Language: English
Date published: 08/01/2018
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Dental Clinic Administration; Pathology; Medical Genetics and Genomics
Record Identifier: 9984025350302771

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