ZMIZ1 lactylation induces tamoxifen resistance in breast cancer through increasing transcriptional activity of Nanog to impact cell stemness and cholesterol uptake

Tamoxifen is a critical drug for the treatment of oestrogen receptor (ER)-positive breast cancer (BC), which represents the majority of BC subtypes. However, many BC tumours that initially respond eventually develop acquired Tamoxifen resistance. Bioinformatics analysis was conducted on genes affected by Tamoxifen and upregulated in Tamoxifen-resistant cells to identify the biological processes associated with Tamoxifen resistance. Metabolomics analysis was conducted to identify the metabolites that were altered in BC with tamoxifen resistance. Resistance to Tamoxifen was evaluated by cell viability, proliferation, invasion, and colony formation in vitro, and by tumour growth in vivo. Metabolomic profiling and the detection of relevant enzymes and metabolites corroborated the metabolic reprogramming towards glycolysis in tamoxifen - resistant BC. The produced lactic acid induced the lactylation of ZMIZ1. This post-translational modification at K843 (but not K537) increased protein stability by suppressing SUMOylation and ubiquitination. The elevated total level of ZMIZ1 increased the enrichment of ZMIZ1 binding to Nanog, resulting in increased transcriptional activity of Nanog, including in OCT4 and NPC2 genes. Therefore, it leads to increased stemness and cholesterol accumulation in Tamoxifen-resistant BC. Knockdown of ZMIZ1 impaired Tamoxifen resistance, but this effect was reversed by Nanog overexpression. In summary, this study identified an important mechanism underlying Tamoxifen resistance and revealed a potential association of glucose glycolysis with cholesterol metabolism through the ZMIZ1/Nanog/NPC2 axis.