Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States
Kieran F Harvey
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
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, United States
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.
