Abstract Background: Epithelial-to-mesenchymal transition (EMT) is critical for development and is implicated in wound healing and cancer metastasis. Cellular plasticity, the ability of a cell to undergo EMT and its reversal mesenchymal-to-epithelial transition (MET), underlies tumor progression through metastasis and acquired chemotherapy resistance through dysregulated gene expression. The epigenetic basis of cancer cell plasticity is partially driven by histone modifying proteins including lysine (K)-specific demethylase 6A (KDM6A). KDM6A is a member of the COMPASS-like protein complex, and catalyzes the removal of methyl groups from H3K27me3, facilitating gene expression. Objectives: Previously we have shown that KDM6A is suppressed upon epithelial to mesenchymal transition (EMT), a form of cellular plasticity that facilitates invasion and dissemination of cancer cells. In this study, we sought to identify how KDM6A expression is regulated and how KDM6A expression and activity are required to maintain epithelial cellular identity. We also identify how KDM6A affects Golgi apparatus morphology as EMT progresses. Methods: To investigate the role of KDM6A in the context of EMT, KDM6A expression was knocked down and immunofluorescence and western blot were utilized to investigate its effects. KDM6A activity was measured using an enzymatic activity assay. Results: We observed that the KDM6A suppression or inhibition profoundly impacts cellular identity, leading to gain of mesenchymal and stemness properties. Moreover, KDM6A was determined to be regulated through sub-cellular localization leading to partial sequestration of COMPASS-like protein complex outside the nucleus, We conclude that KDM6A functions as a master regulator of epithelial cellular identity which is controlled by multi-factorial mechanisms including transcriptional suppression and altered protein localization. Citation Format: C. Worth, A. Nambiar, J. Taube. Kdm6a loss affects epithelial-to-mesenchymal related gene expression and golgi apparatus morphology abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-20.
Worth et al. (Tue,) studied this question.