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

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.

YAP1–TFE3 gene fusion variant in clear cell stromal tumour of lung: report of two cases in support of a distinct entity

“…23 Thus, the predicted fusion protein retains the TEAD binding domain of YAP1 that is essential for tethering the protein to genes to activate transcription and swaps the YAP1 transactivating domain for the basic helix-loop-helix and leucine zipper domains of TFE3, resulting in a constitutively active chimeric transcription factor that elaborates a YAP-like transcriptional programme, as is seen in YAP1-TFE3-fused epithelioid haemangioendothelioma. 24 The structure of the putative YAP1-TFE3 fusion protein found in clear cell stromal tumour is similar to the proposed structures of other YAP1 fusion proteins reported in other entities that encompass exons 1-4 of YAP1. 25 These entities are wideranging and include MUC4-negative sclerosing epithelioid fibrosarcoma (YAP1-KMT2A), 26,27 porocarcinoma (YAP1-NUTM1, YAP1-MAML2), 28 ependymoma (YAP1-MAMLD1, YAP1-FAM118B), 29 meningioma (YAP1-LMO1, YAP1-FAM118B) 30 and retiform and composite haemangioendothelioma (YAP1-MAML2).…”

“…Thus, the resulting fusion product contains the 14–3–3–3 binding site and the WW domains in addition to the TEAD binding sites in YAP1, analogous to WWTR1 ( TAZ ) –CAMTA1 EHE 23 . Thus, the predicted fusion protein retains the TEAD binding domain of YAP1 that is essential for tethering the protein to genes to activate transcription and swaps the YAP1 transactivating domain for the basic helix–loop–helix and leucine zipper domains of TFE3, resulting in a constitutively active chimeric transcription factor that elaborates a YAP‐like transcriptional programme, as is seen in YAP1–TFE3‐fused epithelioid haemangioendothelioma 24 . The structure of the putative YAP1–TFE3 fusion protein found in clear cell stromal tumour is similar to the proposed structures of other YAP1 fusion proteins reported in other entities that encompass exons 1–4 of YAP1 25 .…”

Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma

“…All the YT fusions identified thus far either joined the first exon of YAP1 to the fourth exon of TFE3 , or the first exon of YAP1 to the sixth exon of TFE3. However, this N-terminal portion of YAP still retains the TEAD-binding motif, and, thus, YT fusions can associate with the TEAD family of transcription factors ( Figure 2 ) [ 76 , 77 ]. Furthermore, similar to TAZ, YAP contains five key serine residues that are used by the Hippo pathway to regulate YAP activity ( Figure 2 ) [ 32 , 33 , 38 ].…”

“…The phosphorylation of the other four serine residues (residues other than S127) also leads to an inhibitory effect, albeit to a lesser degree [ 78 ]. In comparison to full-length YAP, the YT fusion contains only one of these five serine residues, and, importantly, S127 is not present in the fusion [ 76 , 77 ]. In contrast, TC contains three of the four regulatory serine sites in TAZ and contains the highly regulated S89 residue [ 75 ].…”

“…In contrast, TC contains three of the four regulatory serine sites in TAZ and contains the highly regulated S89 residue [ 75 ]. Therefore, YT appears to be insensitive to Hippo-pathway activity [ 76 , 77 ].…”