The
hormone prolactin (PRL) contributes to
breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/
signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the
transcription factor STAT5 results in the up-regulation of numerous genes implicated in
breast cancer pathogenesis. However, the molecular mechanisms that enable STAT5 to access the promoters of these genes are not well understood. Here, we show that PRL signaling induces
chromatin decompaction at promoter
DNA, corresponding with STAT5 binding. The
chromatin-modifying
protein high mobility group nucleosomal binding domain 2 (
HMGN2) specifically promotes STAT5 accessibility at promoter
DNA by facilitating the dissociation of the linker
histone H1 in response to PRL. Knockdown of H1 rescues the decrease in PRL-induced transcription following
HMGN2 knockdown, and it does so by allowing increased STAT5 recruitment. Moreover, H1 and STAT5 are shown to function antagonistically in regulating PRL-induced transcription as well as
breast cancer cell biology. While reduced STAT5 activation results in decreased PRL-induced transcription and cell proliferation, knockdown of H1 rescues both of these effects. Taken together, we elucidate a novel mechanism whereby the linker
histone H1 prevents STAT5 binding at promoter
DNA, and the PRL-induced dissociation of H1 mediated by
HMGN2 is necessary to allow full STAT5 recruitment and promote the biological effects of PRL signaling.