Histone deacetylase inhibition and estrogen receptor alpha levels modulate the transcriptional activity of partial antiestrogens

Abstract

In this study, we have analysed the effects of histone deacetylase (HDAC) inhibition on estrogen receptor (ER) expression and on its transcriptional activity in response to antiestrogens. In several breast cancer cell lines, trichostatin A (TSA), a potent HDAC inhibitor, strongly decreases ER expression in a dose-dependent manner. This repression is observed independently of the presence of ligand and also occurs in ovarian and endometrial cell lines. In addition, we show that in MCF7 cells bearing a stably transfected reporter plasmid (MELN cells), partial antiestrogens such as 4-OH-tamoxifen (OHTam), raloxifen or LY117018, switch to an agonist activity upon HDAC inhibition. This effect is blocked by the pure antiestrogen ICI182780 and exhibits a half-maximal concentration of OHTam equivalent to its affinity for ER . The TSA-dependent decrease of ER expression is required to induce the agonist switch of OHTam properties as it is lost in cells constitutively expressing exogenous receptors (MELN-ER or ER ). By contrast, the transrepression activity of OHTam is abolished by TSA independently of the decrease of ER expression. Interestingly, in MELN-ER , ICI182780 remains inhibitory suggesting the involvement of HDAC-independent mechanisms. Finally, in the absence of TSA, transcriptional activity in response to OHTam is significantly raised in MELN cells expressing low levels of ER after transfection of antisense oligonucleotides. In conclusion, inhibition of HDAC enzymatic activity and modulation of ER levels tightly control the relative agonist activity of partial antiestrogens on a stably integrated reporter transgene.

Anti-estrogenic actions of histone deacetylase inhibitors in MCF-7 breast cancer cells

“…In agreement with previous observations (Huang et al 2000, Chopin et al 2002, Margueron et al 2004, HDACi caused an important increase of p21…”

“…Also in agreement with the antagonism on cyclin D1 induction, HDACi were able to block E 2 -dependent pRb phosphorylation, demonstrating again the strong anti-proliferative effects of these inhibitors in estrogen-dependent breast cancer cells. In relation to this, it has been shown that ER-positive breast cancer cells are more sensitive to the HDACi TSA than ER-negative cells (Reid et al 2003, Alao et al 2004, Margueron et al 2004.…”

“…Waf1/Cip1 in breast cancer cells (Chopin et al 2002, Alao et al 2004, Margueron et al 2004. It is becoming clear that ER and HDACi pathways crosstalk at various levels such as expression and activity of ERa, regulation of p21 Waf1/Cip1 expression, cell proliferation, etc.…”

Scaffold attachment factor B1 directly interacts with nuclear receptors in living cells and represses transcriptional activity

“…We show here that SAFB action is specifically affected by four different HDAC inhibitors, depending on the receptor tested (FXR or PPAR). Although these results may appear confusing at first sight, they most probably reflect the recruitment of different types of HDACs by each receptor, as well as some specific interplay between HDACs on the one hand and promoters and ligands on the other hand, as recently exemplified with the estrogen receptor (ER), whose action is differently modulated by HDAC inhibitors, depending upon the cell line and the ligand tested (Margueron et al 2004). It is also possible that these compounds have some side effects and modulate other cellular components which indirectly affect the transcription of the reporter construct.…”

Specific Activity of Class II Histone Deacetylases in Human Breast Cancer Cells

“…In breast tumor models, HDIs have potent antiproliferative effects in vitro and in vivo and interfere with estrogen signaling (13)(14)(15)(16)(17). Estrogens effects are mediated by two distinct estrogen receptors, ERa and ERh, acting as transcriptional factors that belong to the nuclear receptor superfamily (18).…”