Abstract PS16-07: Blocking H3K27me3 methyltransferase or demethylase activity impacts epithelial-mesenchymal plasticity, suppressing tumor growth and metastasis
Authors: Joseph Taube, Provas Das, Kelsey Johnson, John Landua, Lacey Dobrolecki, Michael Lewis
Journal: Cancer Research (2021)

Abstract Background: Epithelial-mesenchymal plasticity (EMP) is key feature driving breast cancer metastasis. Induction of epithelial-mesenchymal transition (EMT) increases the migratory and invasive capabilities associated with metastatic competence and endows tumors with stem cell properties necessary for initiating tumor growth in the metastatic site. Mesenchymal-epithelial transition (MET) has been increasingly recognized as an integral part of the latter stages of the metastatic cascade as it is required for re-epithelialization, proliferation, and expansion of micro-metastases into macro-metastases with a histopathology similar to that of the primary tumor. Interconversion between epithelial and mesenchymal states requires remodeling of the epigenome–including addition and erasure of H3K27me3, especially near gene promoter and enhancers. Deposited by EZH1 or EZH2, members of the PRC2 complex, H3K27me3 is associated with gene silencing. However, gene activation occurs upon H3K27me3 demethylation to H3K27me1, mediated by KDM6A or KDM6B, members of the Compass-like complex. Results: Based upon our prior work, which showed EMT-driven re-distribution of H3K27me3 onto and off of genes that are critical regulators of cell fate and differentiation, we asked whether inhibition of H3K27me3-directed methyltransferases and demethylases could impact breast cancer. We found that the EZH2 inhibitor, EPZ011989, reduced EMP by preventing recovery of epithelial trails in cells exposed to TGFβ, but did not, on its own, induce EMT. However, we found that either inhibition of the H3K27me3-directed demethylases, KDM6A and KDM6B, using GSK-J4 or shRNA knockdown, induced EMT and promoted cellular migration. Thus, manipulation of either EZH2 or KDM6A/B affected the capacity of cells to repress or activate expression of genes known to exhibit dynamic gain or loss of H3K27me3 during EMT. Given the effects of inhibitors of H3K27-targeted enzymes on EMP, we sought to ascertain their impact on tumor growth and metastasis. Using a GFP-expressing patient-derived xenograft (PDX) model of ER-positive breast cancer, we observed a dose-dependent suppression of primary tumor growth and fewer disseminated tumor cells (DTCs) in response to small molecules targeting H3K27me3 regulators. Conclusions: These results indicate that addition and removal of H3K27me3 is critical for maintenance of cell fate and plasticity. Furthermore, targeting this pathway suppresses breast cancer growth and metastasis in a mouse model of ER-positive breast cancer. Citation Format: Joseph Taube, Provas Das, Kelsey Johnson, John Landua, Lacey Dobrolecki, Michael Lewis. Blocking H3K27me3 methyltransferase or demethylase activity impacts epithelial-mesenchymal plasticity, suppressing tumor growth and metastasis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-07.