HMGA1 Regulates the Expression of Replication-Dependent Histone Genes and Cell-Cycle in Breast Cancer Cells

Breast cancer (BC) is the primary cause of cancer mortality in women and the triple-negative breast cancer (TNBC) is the most aggressive subtype characterized by poor differentiation and high proliferative properties. High mobility group A1 (HMGA1) is an oncogenic factor involved in the onset and progression of the neoplastic transformation in BC. Here, we unraveled that the replication-dependent-histone (RD-HIST) gene expression is enriched in BC tissues and correlates with HMGA1 expression. We explored the role of HMGA1 in modulating the RD-HIST genes expression in TNBC cells and show that MDA-MB-231 cells, depleted of HMGA1, express low levels of core histones. We show that HMGA1 participates in the activation of the HIST1H4H promoter and that it interacts with the nuclear protein of the ataxia-telangiectasia mutated locus (NPAT), the coordinator of the transcription of the RD-HIST genes. Moreover, we demonstrate that HMGA1 silencing increases the percentage of cells in G0/G1 phase both in TNBC and epirubicin resistant TNBC cells. Moreover, HMGA1 silencing causes an increase in epirubicin IC₅₀ both in parental and epirubicin resistant cells thus suggesting that targeting HMGA1 could affect the efficacy of epirubicin treatment.