Inhibition of the MLL1-WDR5 interaction modulates epithelial to mesenchymal transition and metabolic pathways in triple-negative breast cancer cells

Histone methylation is a key epigenetic modulation that regulates gene expression and is often associated with the pathogenesis of various cancers, including triple-negative breast cancer (TNBC). Histone methyltransferase, MLL1-WDR5 complex regulates gene transcription by catalyzing trimethylation of lysine 4 on histone H3 (H3K4me3) and promotes carcinogenesis. Herein, epithelial-to-mesenchymal transition (EMT) in TNBC cells is shown to facilitate upregulation of MLL1 and WDR5 expression by 4.7-fold and 3.84-fold, thereby establishing the association of these proteins in EMT dynamics. Therefore, we explored the therapeutic potential of inhibiting MLL1-WDR5 interaction using the small molecule inhibitor MM-102 in TNBC cell lines. MLL1 inhibition significantly reduced H3K4me3 levels and enhanced the apoptotic population by 30 % in MDA-MB-468 cells, demonstrating its cytotoxic potential. Notably, MM-102 treatment reverses the EMT process by upregulating the expression of epithelial markers (such as E-cadherin and claudin) and downregulating the expression of mesenchymal markers (such as beta-catenin, Slug, caveolin 1, and fibronectin). In addition, MLL1 inhibition caused a metabolic shift, with a 5-fold increase in ALDO A and a 4-fold increase in ENO1 expression, indicating enhanced glycolysis. Further reduction in the fatty acid uptake and lipid droplet accumulation by MM-102 treatment signifies that targeting MLL1 also rewires the metabolic network in TNBC cells. Collectively, inhibiting MLL1 represents a promising therapeutic strategy for managing EMT-driven metastasis, reshaping metabolic reprogramming, and ultimately improving therapeutic outcomes in aggressive breast cancer.