The role of lysine histone demethylase KDM5B isoform on cellular migration and transcription regulation in breast cancer

Histone Lysine Demethylases (KDMs) regulate gene expression and other biological processes as DNA repair and damage checkpoint activation. KDMs deregulation in tumour environments contributes to cancer development and progression. Specifically, KDM5B, acting on H3K4me3, is up regulated in several cancer types, including breast cancer. It is still unknown what contextual factors make the demethylases functioning as oncogenes or tumour suppressors. The presence of different isoforms and their relative amount may define their behaviour in the tumour context. In breast cancer, the existence of a KDM5B-N-terminal truncated (NTT) isoform has been recently demonstrated (Di Nisio et al., 2023). NTT’s truncation affects the whole JmjN and part of the ARID domains. Thus, it lacks the demethylase activity, but it could maintain the ability to bind the H3 tails through PHD domains, maybe acting as a negative dominant competitor for the canonical KDM5B-PLU1 isoform. Since the ratio between PLU1 and NTT is variable in different cancer cell lines, it is relevant to understand its regulatory roles. One of the main processes that involve KDM5Bmediated regulation is cell migration. In this study, we investigated the effects of the overexpression of NTT or PLU1 on migration in breast cancer cell lines. NTT-overexpressing MCF7 cells significantly increased their migratory potential compared to PLU1- overexpressing or empty vector-transfected ones. MDA-MB-231 showed the same trend even if the observed differences were not statistically significant. However, previously performed RNAseq experiments highlighted a strong involvement of epithelial-mesenchymal transition (EMT) pathways in the transcriptome of breast cancer cells overexpressing NTT. Thus, we are further investigating the expression of these differentially expressed genes which could be related to the phenotype.