Histone deacetylase inhibitors suppress transdifferentiation of gonadotrophs to prolactin cells and proliferation of prolactin cells induced by diethylstilbestrol in male mouse pituitary

Abstract

Diethylstilbestrol (DES), an estrogen agonist, increases prolactin (PRL) cells through transdifferentiation of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) cells to PRL cells as well as proliferation of PRL cells in adult male mouse pituitary. Since hyperacetylation of histone H3 is implicated in the regulation of activation of various genes, we examined the effect of DES on the state of histone H3 acetylation. DES significantly reduced the immunohistochemical signal for acetylated histone H3 at lysine 9 (H3K9ac) in PRL, LH and FSH cells, but not for H3K18ac or H3K23ac. DES-treated mice were injected intraperitoneally with HDAC inhibitors (HDACi), sodium phenylbutyrate (NaPB) or valproic acid (VPA), to mimic the acetylation level of histone H3. As expected, HDACi treatment restored the level of H3K9ac expression in these cells, and also inhibited DES-induced increase in PRL cells. Furthermore, NaPB and VPA also abrogated the effects of DES on the population density of both LH and FSH cells. Similarly, the numbers of proliferating and apoptotic cells in the pituitary in NaPB-or VPA-treated mice were comparable to those of the control mice. Considered together, these results indicated that the acetylation level of histone H3 plays an important role in DES-induced transdifferentiation of LH to PRL cells as well as proliferation of PRL cells.

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“…Secondly, VPA, as a histone deacetylase inhibitor, may inhibit the transcription of the GnRH1 gene in the hypothalamus and promote changes in the plasticity of GnRH neurons (77). This effect can also reverse the differentiation of LH and FSH cells into PRL cells, resulting in abnormal sex hormone levels and destruction of the hypothalamic-pituitary-gonadal (HPG) axis (78). Thirdly, the increased level of leptin and the decreased level of adiponectin in patients treated with VPA (79-82) and their receptors were expressed in the hypothalamus and pituitary (83).…”

In focus in HCB

“…Since it is known that DES acts through binding to ERα and that this interaction changes the acetylation state of lysine residues in histones (Fiskus et al 2007;Kuo and Allis 1998;Strasak et al 2009), they investigated the degree of histone H3 acetylation in the pituitary gland of DES-treated mice as compared to control animals. In a first step, Tun et al (2019) studied the acetylation level of histone H3 by single and double labeling immunohistochemistry. In control mice, strong nuclear staining for acetylated histone H3K9 was observed in PRL, LH and FSH cells.…”