H2A.Z overexpression promotes cellular proliferation of breast cancer cells.
We recently showed that histone H2A.Z, as well as members of the ATP-dependent p400 chromatin remodeling complex (p400.com), are essential components of estrogen receptor alpha (ERalpha) signaling. More specifically, we showed that H2A.Z and p400.com are incorporated into the promoter regions of ERalpha target genes only upon gene induction, and also in a cyclic fashion. RNAi-mediated cellular depletion of H2A.Z and p400.com strongly impedes estrogen-dependent growth of breast cancer cells as well as strongly affect ERalpha-target gene expression. Two mechanisms emerged from our studies of how H2A.Z incorporation within ERalpha-target regulatory regions can actually regulate estrogen-mediated signaling: (1) by stabilizing nucleosomes within the translational DNA axis, a process that allows general transcription factors to be efficiently recruited to promoter regions; (2) by allowing estrogen-responsive enhancer function. In the current study, we now show that in MCF7 cells, ectopic overexpression of H2A.Z increases proliferation, and such in conditions where estrogen levels are low. Also, immunohistochemical studies of breast cancer biopsies show that the presence of H2A.Z correlates highly with that of ERalpha, but is associated with high-grade ER-negative cancers. Finally we show that ERalpha directly associates to the H2A.Z promoter, and consequently modulates its expression. Our study provides a possible link between H2A.Z and endocrine resistance by showing that H2A.Z overexpression leads to increased growth, particularly when estrogen levels are very low.
Svotelis
Amy
A
Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, QC, CA.
Gévry
Nicolas
N
Grondin
Gilles
G
Gaudreau
Luc
L
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D016196:S Phase
D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones