TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers.
The accession number for the RNA-Seq data reported in this paper for NIH 3T3 cells is GEO: GSE152736. The accession number for the RNA-Seq data reported in this paper for SW872 cells is GEO: GSE152737. The accession number for the ChIP-Seq data reported in this paper is GEO: GSE152778. The accession number for the ATAC-Seq data reported in this paper is GEO: GSE152733. The accession number for the H3K27ac ChIP-Seq data reported in this paper is GEO: GSE168201. The accession number for the RNA-Seq data after YEATS2 and ZZZ3 knock-down is GEO: GSE168205.
Article and author information
Veterans Health Administration Merit Review Program (1 I01 BX003644-01)
- Munir R Tanas
National Institutes of Health (R01 CA237031-01A1)
- Munir R Tanas
National Health and Medical Research Council (APP1078220)
- Kieran F Harvey
Canadian Institutes of Health Research (FDN 144301)
- Anne-Claude Gingras
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (#9052228-008 ) of the University of Iowa. All injections for mouse xenograft experiments were performed under isoflurane anesthesia, and every effort was made to minimize suffering.
- Joaquín M Espinosa, University of Colorado Anschutz Medical Campus, United States
- Received: September 7, 2020
- Accepted: April 28, 2021
- Accepted Manuscript published: April 29, 2021 (version 1)
- Version of Record published: May 24, 2021 (version 2)
- Version of Record updated: May 28, 2021 (version 3)
© 2021, Merritt et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
- Page views
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
- Cancer Biology
In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153D and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRASG12D-driven ERMS-model.
- Cancer Biology
The presence of lymph node metastasis (LNM) affects treatment strategy decisions in T1NxM0 colorectal cancer (CRC), but the currently used clinicopathological-based risk stratification cannot predict LNM accurately. In this study, we detected proteins in formalin-fixed paraffin-embedded (FFPE) tumor samples from 143 LNM-negative and 78 LNM-positive patients with T1 CRC and revealed changes in molecular and biological pathways by label-free liquid chromatography tandem mass spectrometry (LC-MS/MS) and established classifiers for predicting LNM in T1 CRC. An effective 55-proteins prediction model was built by machine learning and validated in a training cohort (N=132) and two validation cohorts (VC1, N=42; VC2, N=47), achieved an impressive AUC of 1.00 in the training cohort, 0.96 in VC1 and 0.93 in VC2, respectively. We further built a simplified classifier with nine proteins, and achieved an AUC of 0.824. The simplified classifier was performed excellently in two external validation cohorts. The expression patterns of 13 proteins were confirmed by immunohistochemistry, and the IHC score of five proteins was used to build an IHC predict model with an AUC of 0.825. RHOT2 silence significantly enhanced migration and invasion of colon cancer cells. Our study explored the mechanism of metastasis in T1 CRC and can be used to facilitate the individualized prediction of LNM in patients with T1 CRC, which may provide a guidance for clinical practice in T1 CRC.