TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex

eLife

Nicholas Borcherding¹  Nicole Merritt²  Colleen Fullenkamp²  Keith Garcia³  Munir R Tanas⁴  Michael S Chimenti⁵  Anne-Claude Gingras⁶  Dushyandi Rajendran⁶  Zhen-Yuan Lin⁶  Xiaomeng Zhang⁷  Katrina A Mitchell⁸  Kieran F Harvey⁹ 

[1] Department of Pathology and Immunology, Washington University, St. Louis, United States;Department of Pathology, University of Iowa, Iowa City, United States;Department of Pathology, University of Iowa, Iowa City, United States;Cancer Biology Graduate Program, University of Iowa, Iowa City, United States;Department of Pathology, University of Iowa, Iowa City, United States;Cancer Biology Graduate Program, University of Iowa, Iowa City, United States;Holden Comprehensive Cancer Center, University of Iowa, Iowa City, United States;Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Iowa City, IA, United States;Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, United States;Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States;Peter MacCallum Cancer Centre, Melbourne, Australia;Peter MacCallum Cancer Centre, Melbourne, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia;Peter MacCallum Cancer Centre, Melbourne, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia;Department of Anatomy and Developmental Biology and Biomedicine Discovery Institute, Monash University, Clayton, Australia;

关键词: hippo pathway;    sarcomas;    chimeric transcription factors;    fusion proteins;    epigenetics;    ATAC complex;    Human;    Mouse;   

DOI  :  10.7554/eLife.62857

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY