KDM6A Depletion in Breast Epithelial Cells Leads to Reduced Sensitivity to Anticancer Agents and Increased TGF beta Activity

KDM6A, an X chromosome-linked histone lysine demethylase, was reported to be frequently mutated in many tumor types including breast and bladder cancer. However, the functional role of KDM6A is not fully understood. Using MCF10A as a model of non-tumorigenic epithelial breast cells, we found that silencing KDM6A promoted cell migration and transformation demonstrated by the formation of tumor-like acini in three-dimensional culture. KDM6A loss reduced the sensitivity of MCF10A cells to therapeutic agents commonly used to treat patients with triple-negative breast cancer and also induced TGF beta extracellular secretion leading to suppressed expression of cytotoxic genes in normal human CD8(+) T cells in vitro. Interestingly, when cells were treated with TGFb, de novo synthesis of KDM6A protein was suppressed while TGFB1 transcription was enhanced, indicating a TGF beta/KDM6A-negative regulatory axis. Furthermore, both KDM6A deficiency and TGF beta treatment promoted disorganized acinar structures in three-dimensional culture, as well as transcriptional profiles associated with epithelial-to-mesenchymal transition and metastasis, suggesting KDM6A depletion and TGF beta drive tumor progression.