Abstract 4097: The ATAC histone acetyltransferase complex is a key oncogenic driver in sarcomas

Abstract Background: Sarcomas are heterogenous neoplasms originating in mesenchymal tissues such as muscles, fat, nerves, blood vessels, etc. Our lab has previously shown that the Hippo signaling pathway is perturbed in sarcomas, and TAZ/YAP, the end effectors of the Hippo pathway, are key oncoproteins driving sarcomagenesis. Epithelioid hemangioendothelioma (EHE), a vascular sarcoma, is predominantly driven by the fusion protein TAZ-CAMTA1, which promotes cancer hallmarks and alters gene expression patterns by interacting with YEATS2 and ZZZ3, which are key scaffolds of the Ada2A-Containing (ATAC) histone acetyltransferase (HAT) complex. YEATS2 is a histone reader and binds H3K27-acetyl, and ZZZ3 binds the histone H3 tail, and both YEATS2 and ZZZ3 are necessary for the proper assembly of the ATAC complex, which subsequently acetylates H3K9, a key histone modification necessary for gene transcription. Previously, we have utilized RNA-sequencing data from The Cancer Genome Atlas and shown that high YEATS2/ZZZ3 RNA levels correlate with a worse overall survival in multiple histological subtypes of sarcomas. Methods: We performed western blot analysis to measure YEAST2/ZZZ3 protein levels in human sarcoma cell lines. We utilized siRNA/shRNA to knockdown YEATS2/ZZZ3 and measured H3K9-acetyl protein levels via western blot analysis. Apart from genetic inhibition, we utilized HAT-inhibitors and performed several in vitro cancer hallmarks, such as 3D soft agar assays and poly-HEMA assays to measure anchorage-independent growth and MTT-based assays to measure 2D proliferation. We also performed a cell-line-derived xenograft experiment where we injected immunocompromised NSG mice with SW872 cells expressing TAZ-CAMTA1 with or without stable knockdown of YEATS2. Results: We observed that YEATS2/ZZZ3 protein levels are upregulated in multiple human sarcoma cells. We also observed that genetic and pharmacological inhibition of the ATAC complex in both fusion protein-positive (SW872 cells expressing TAZ-CAMTA1) and -negative (SKLMS; leiomyosarcoma and HT1080; fibrosarcoma) sarcoma cells decreases H3K9-acetyl protein levels. In the xenograft experiment, knockdown of YEATS2 significantly decreased tumor initiation and progression in NSG mice as compared to non-targeting cells. In SKLMS, YEATS2 knockdown significantly reduced 2D proliferation and colony formation on soft agar. Conclusion: Our data show that in both fusion protein-positive and -negative sarcomas, the ATAC complex is a key histone acetyltransferase for H3K9. We show that the ATAC complex promotes tumorigenesis in vivo in a xenograft mouse model. In the leiomyosarcoma cell line SKLMS, the ATAC complex promotes 2D proliferation and anchorage-independent growth in vitro, which are key cancer hallmarks. Overall, our studies show that the ATAC complex is a potential therapeutic target in multiple sarcomas, such as EHE and leiomyosarcoma. Citation Format: Souradip Sinha, Krishnendu Ghosh, Ali Khan, Yuliia Drebot, Gillian DeWane, Nicholas Scalora, Samuel Yu, Keith Garcia, Munir R. Tanas. The ATAC histone acetyltransferase complex is a key oncogenic driver in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4097.