Abstract 2129: Usp22 controls multiple signaling pathways in development and disease

Abstract Our research is focused on defining the functions of histone-modifying enzymes in normal cells so that we can understand how alterations in these activities contribute to tumor development or progression. The highly conserved SAGA complex plays important roles at multiple steps of gene transcription in yeast, flies, and mammalian cells. This modular complex houses two enzymatic activities, the GCN5 histone acetyltransferase, and the USP22 deubiquitinase. USP22 is overexpressed in highly aggressive, therapy-resistant cancers, but the normal functions of this deubiquitinase are not well defined. Our detailed analysis of the embryonic lethality observed in the Usp22-/- mouse model we generated highlighted a critical role for Usp22 in the developing placenta. We found that Usp22 deletion in mice results in embryonic lethality due to defects in the formation and organization of extra-embryonic placental tissues, culminating in failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFß and several receptor tyrosine kinase (RTK) pathways. Interestingly, overexpression of USP22 in mice leads to an over branching phenotype of the mammary gland, which is linked to the deregulation of the signaling pathways described above. Our results provide insights to potential angiogenic functions of the SAGA complex, indicate that Usp22 is critical for the proper execution of multiple signaling pathways important for normal development, and provide new clues towards Usp22 contributions to cancer and other disease states. Citation Format: Evangelia Koutelou, Xianghong Kuang, Sharon Y. Dent. Usp22 controls multiple signaling pathways in development and disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2129.