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Epigenetic dysregulation has recently been recognized as a new hallmark of cancer. Dysregulation of chromatin remodelers is estimated to affect 10-20% of cancer. Thus, understanding how epigenetic-based mechanisms contribute to cancer initiation and progression is critical. KMT5C is a histone methyltransferase that catalyzes histone H4 lysine 20 trimethylation (H4K20me3), which has historically been associated with formation and maintenance of constitutive heterochromatin regions. Albeit recent evidence from our lab also suggests regulation of gene-rich euchromatin regions. In this previous body of work we discovered that loss of KMT5C promotes development of resistance to tyrosine kinase inhibitors (TKI) in EGFR-mutant non-small cell lung cancer (NSCLC) cells (PC9 and HCC827). Patient data further supports that the KMT5C transcript level is downregulated following resistance to osimertinib, a third-generation TKI. Our data suggests that KMT5C is involved in non-canonical regulation of genes outside of heterochromatic regions through its methyltransferase activity. Analysis of data deposited into the Cell Miner database and publicly available RNA-sequencing and ChIP-sequencing data revealed that the KMT5C-H4K20me3 axis has significant negative correlations with several genes involved in epithelial-to-mesenchymal transition (EMT). Our validation studies support this observation. However the mechanisms involved in KMT5C facilitating this change at EMT-related genes is unknown. KMT5C is well understood to be recruited to heterochromatin regions through its interaction with HP1, yet the mechanism for recruitment of KMT5C to gene-rich euchromatin regions remains to be elucidated. We hypothesize that KMT5C is recruited to its target genes in euchromatin in an HP1-independent mechanism. In this study, we aim to identify the interactome of KMT5C using an unbiased proximity labeling BioID approach. This study is expected to uncover a novel epigenetic mechanism that contributes to development of resistance to TKIs and may inform of strategies to target KMT5C-downregulated TKI-resistant cancers. Citation Format: Jihye Son, Alejandra Agredo, Ally Glaws, Andrea L. Kasinski. KMT5C-dependent regulation of mesenchymal-related genes and identification of KMT5C interactome using BioID. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4726. |
