Synergistic Induction of Galectin-1 by CCAAT/Enhancer Binding Protein α and Hypoxia-inducible Factor 1α and Its Role in Differentiation of Acute Myeloid Leukemic Cells

Galectin-1 is a member of the galectin family and has a high affinity for galactose and N-acetylglucosamine moieties of glycoproteins. It mediates multiple signal transduction pathways to modulate cellular proliferation, survival, differentiation, and migration. However, the mechanisms for the regulation of its expression remain greatly elusive. We reported previously that galectin-1 is a direct target of the hypoxia-inducible factor 1 (HIF-1), a key heterodimeric transcriptional factor for the cellular response to hypoxia. Here we show that CCAAT/enhancer binding protein alpha (C/EBP alpha), a critical transcriptional factor for hematopoietic cell differentiation, can directly activate galectin-1 through binding to the -48 to -42 bp region of its promoter. Based on the physical interaction of C/EBP alpha and HIF-1 1 alpha, the synergistic transcriptional activity of C/EBP alpha and HIF-1 alpha on the promoter of the galectin-1 gene is also found by chromatin immunoprecipitation (ChIP), ChIP followed by ChIP (ChIP-reChIP), and luciferase assay. Moreover, knockdown or chemical inhibition of galectin-1 partially blocks the differentiation induced by HIF-1 alpha or C/EBP alpha, which can be rescued by recombinant galectin-1. These discoveries would shed new insights on the mechanisms for galectin-1 expression regulation and HIF-1 alpha- and C/EBP alpha-induced leukemic cell differentiation.