Estrogen activation on histone H3 lysine 79 dimethylation mediated menin and chromatin interaction in breast cancer

Abstract

Breast cancer is one of the most prevalent cancer diagnoses worldwide. To address the heterogeneity in breast cancer therapy, these cancers are classified into distinct molecular subclasses. ER signaling is a fundamental driver in ER-positive (ER+) breast cancer subtypes. Inhibition of ER signaling remains a principal treatment strategy, markedly enhancing patient survival rates in ER+ breast cancer cases. Epigenetic modulations, particularly those involving coactivator and corepressor complexes, are also integral to the transcriptional regulation underlying breast cancer oncogenesis, tumor expansion, and progression. Within this context, DOT1L, an enzyme responsible for the methylation (both mono, di, and tri-methylation) of histone H3 on lysine-79 (H3K79me), has been recognized as a vital constituent of these multiprotein complexes. Moreover, menin a part of the MLL1/MLL2 (lysine methyltransferase) complexes, is capable of interactive activation with ER to act as a key driver in approximately 70% of sporadic breast cancer cases. Recent advances in the development of nucleosome-based photoaffinity probes, in tandem with quantitative proteomics, have pinpointed menin as a specific "reader" of di-methylated H3K79 (H3K79me2). Within cells, menin demonstrates selective affinity for chromatin regions enriched with H3K79me2. The administration of the DOT1L inhibitor resulted a near-complete eradication of global H3K79me2 levels, consequently disrupting the menin-chromatin interaction. Interestingly, after exogenous estrogen dosage, it was discovered that the persistence of menin-chromatin interaction, notwithstanding the presence of DOT1L inhibition. To explore the dynamics between epigenetic modulations and hormone receptor interactions, proteomic and genomic approaches will be employed to elucidate the influence of estrogen activation on H3K79me2 - mediated menin/chromatin interplay and to unravel the interaction mechanisms of menin - Dot1L - ERα on chromatin in breast cancer cells.