TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex
| Autor: | Zhen-Yuan Lin, Nicholas Borcherding, Munir R. Tanas, Colleen Fullenkamp, Katrina A. Mitchell, Nicole Merritt, Dushyandi Rajendran, Xiaomeng Zhang, Michael S. Chimenti, Keith Garcia, Anne-Claude Gingras, Kieran F. Harvey |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mouse Cell Cycle Proteins Fusion gene Transcriptome Mice 0302 clinical medicine Gene expression Biology (General) sarcomas Cancer Biology Histone Acetyltransferases Basic Helix-Loop-Helix Leucine Zipper Transcription Factors General Neuroscience Intracellular Signaling Peptides and Proteins General Medicine Chromosomes and Gene Expression Cell biology 030220 oncology & carcinogenesis chimeric transcription factors Hemangioendothelioma Epithelioid Medicine Research Article Human Protein Binding Histone acetyltransferase complex hippo pathway QH301-705.5 Science Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Animals Humans Epigenetics Hippo signaling pathway General Immunology and Microbiology epigenetics Calcium-Binding Proteins Fusion protein 030104 developmental biology Transcriptional Coactivator with PDZ-Binding Motif Proteins Cancer cell Trans-Activators fusion proteins ATAC complex Transcription Factors |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| Popis: | 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. eLife digest The proliferation of human cells is tightly regulated to ensure that enough cells are made to build and repair organs and tissues, while at the same time stopping cells from dividing uncontrollably and damaging the body. To get the right balance, cells rely on physical and chemical cues from their environment that trigger the biochemical signals that regulate two proteins called TAZ and YAP. These proteins control gene activity by regulating the rate at which genes are copied to produce proteins. If this process becomes dysregulated, cells can grow uncontrollably, causing cancer. In cancer cells, it is common to find TAZ and YAP fused to other proteins. In epithelioid hemangioendothelioma, a rare cancer that grows in the blood vessels, cancerous growth can be driven by a version of TAZ fused to the protein CAMTA1, or a version of YAP fused to the protein TFE3. While the role of TAZ and YAP in promoting gene activity is known, it is unclear how CAMTA1 and TFE3 contribute to cell growth becoming dysregulated. Merritt, Garcia et al. studied sarcoma cell lines to show that these two fusion proteins, TAZ-CAMTA1 and YAP-TFE3, change the pattern of gene activity seen in the cells compared to TAZ or YAP alone. An analysis of molecules that interact with the two fusion proteins identified a complex called ATAC as the cause of these changes. This complex adds chemical markers to DNA-packaging proteins, which control which genes are available for activation. The fusion proteins combine the ability of TAZ and YAP to control gene activity and the ability of CAMTA1 and TFE3 to make DNA more accessible, allowing the fusion proteins to drive uncontrolled cancerous growth. Similar TAZ and YAP fusion proteins have been found in other cancers, which can activate genes and potentially alter DNA packaging. Targeting drug development efforts at the proteins that complex with TAZ and YAP fusion proteins may lead to new therapies. |
| Databáze: | OpenAIRE |
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