TY - JOUR
T1 - PI3K/mTOR mediate mitogen-dependent HDAC1 phosphorylation in breast cancer
T2 - A novel regulation of estrogen receptor expression
AU - Citro, Simona
AU - Miccolo, Claudia
AU - Meloni, Laura
AU - Chiocca, Susanna
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Histone deacetylase 1(HDAC1) is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure. Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer. Downregulation of estrogen receptor a (ERa) expression is one of the mechanisms behind the acquisition of endocrine resistance. Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy. Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer, reversing also acquired hormone resistance. Here we show how mitogens, activating the PI3K/mTOR pathway, trigger the phosphorylation of HDAC1 in breast cancer cells, which is completely dependent on the activity of the p70 S6 kinase (S6K1). Our findings show that S6K1, overexpressed in many breast cancers, controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli, controlling HDAC1 recruitment to the ERa promoter. Furthermore, cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation. This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.
AB - Histone deacetylase 1(HDAC1) is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure. Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer. Downregulation of estrogen receptor a (ERa) expression is one of the mechanisms behind the acquisition of endocrine resistance. Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy. Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer, reversing also acquired hormone resistance. Here we show how mitogens, activating the PI3K/mTOR pathway, trigger the phosphorylation of HDAC1 in breast cancer cells, which is completely dependent on the activity of the p70 S6 kinase (S6K1). Our findings show that S6K1, overexpressed in many breast cancers, controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli, controlling HDAC1 recruitment to the ERa promoter. Furthermore, cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation. This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.
KW - breast cancer
KW - estrogen receptor
KW - HDAC1/mTOR/PI3K/S6K1
UR - http://www.scopus.com/inward/record.url?scp=84929857962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929857962&partnerID=8YFLogxK
U2 - 10.1093/jmcb/mjv021
DO - 10.1093/jmcb/mjv021
M3 - Article
C2 - 25801958
AN - SCOPUS:84929857962
VL - 7
SP - 132
EP - 142
JO - Journal of Molecular Cell Biology
JF - Journal of Molecular Cell Biology
SN - 1674-2788
IS - 2
ER -