Abstract
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.
Highlights
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that arises over a wide age range and can occur essentially anywhere anatomically
TFE3 is a member of the Microphthalmia-associated transcription factor (MiTF) family of basic helix-loop-helix containing transcription factors, consisting of four structurally similar genes (TFE3, TFE3B, TFEC, and MITF), that are involved in regulating tissue-specific functions of cell differentiation (Kauffman et al, 2014; Steingrimsson et al, 2002)
We find that each fusion protein drives a related but distinct transcriptional program, which is underpinned by the fact that they both engage the genome at least in part via the TEA domain (TEAD) transcription factors, as do wild-type YAP and TAZ
Summary
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that arises over a wide age range and can occur essentially anywhere anatomically. When it occurs in the lung or the liver, it frequently presents with metastasis early in its clinical course (Goldblum and Weiss, 2014). The WWTR1CAMTA1 gene fusion is encoded by a t(1;3)(p36;q25) chromosomal translocation (Errani et al, 2011, Tanas et al, 2011; Tanas et al, 2016) resulting in a TAZ-CAMTA1 fusion protein present in 85–90% of all EHE tumors (Errani et al, 2011; Tanas et al, 2011).
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