HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells

in Journal of Molecular Endocrinology
Correspondence should be addressed to D J Bernard: daniel.bernard@mcgill.ca
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Fertility is dependent on follicle-stimulating hormone (FSH), a product of gonadotrope cells of the anterior pituitary gland. Hypothalamic gonadotropin-releasing hormone (GnRH) and intra-pituitary activins are regarded as the primary drivers of FSH synthesis and secretion. Both stimulate expression of the FSH beta subunit gene (Fshb), although the underlying mechanisms of GnRH action are poorly described relative to those of the activins. There is currently no consensus on how GnRH regulates Fshb transcription, as results vary across species and between in vivo and in vitro approaches. One of the more fully developed models suggests that the murine Fshb promoter is tonically repressed by histone deacetylases (HDACs) and that GnRH relieves this repression, at least in immortalized murine gonadotrope-like cells (LβT2 and αT3-1). In contrast, we observed that the class I/II HDAC inhibitor trichostatin A (TSA) robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LβT2 cells and in primary murine pituitary cultures. Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II-specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene.

 

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    HDAC inhibition impairs basal, GnRH-, and activin A-induced Fshb expression. (A, B and C) LβT2 cells were treated for 2 h with GnRH (10 nmol/L) in the presence or absence of TSA (331 nmol/L), followed by incubation in GnRH-free medium for an additional 2 h, in the presence or absence of TSA. n = 3 independent experiments. (A) Fshb, (B) Fos, and (C) Egr1 mRNA levels were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. (D) LβT2 cells were treated for 6 h with activin A (1 nmol/L) in the presence or absence of TSA (331 nmol/L). n = 5 independent experiments. Fshb mRNA levels were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. (E) and (F) Cells were treated as in panel D and RNA was collected after 2, 6 or 24 h of treatment. n = 3 independent experiments. Fshb and Lhb mRNA levels were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. For each time point, data were normalized to the control condition. In all panels, bars represent mean values (± s.e.m.). Activin A’s fold induction is indicated above the appropriate bars. Data were analyzed by two-way ANOVAs followed by a post-hoc Holm–Sidak multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001 when comparing activin A vs control; ###P < 0.001 when comparing TSA vs corresponding vehicle condition.

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    Class I, but not class II, HDAC inhibition inhibits activin A-induced Fshb mRNA levels. (A) LβT2 cells were treated for 6 h with a class I (entinostat) or a class II HDAC inhibitor (MC1568), at a concentration of 42.5 μmol/L and 2.5 μmol/L, respectively (n = 4). (B) LβT2 cells were treated in separate experiments for 6 h with TMP269, a second class II HDAC inhibitor, at a concentration of 3.9 μmol/L (N = 2). In (A) and (B), Fshb mRNA levels were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. Activin A’s fold induction is indicated above the appropriate bars in panel A. (C and D) LβT2 cells were treated for 6 h with vehicle (DMSO), TSA (45 nmol/L), entinostat (42.5 μmol/L), or TMP269 (3.9 μmol/L). Total protein lysates were extracted and levels of acetylated H4K12 (panel C), acetylated α-tubulin (panel D), and α-tubulin (panels C and D) were analyzed by western blot. (E) C2C12 cells were treated for 24 h with vehicle (DMSO), MC1568 (2.5 μmol/L), or TSA (45 nmol/L) in GM. After incubation, cells were grown for another 24 h in GM or differentiation medium (DM) in the presence of vehicle (DMSO), MC1568 (2.5 μmol/L), or TSA (45 nmol/L). Myog mRNA levels were measured by RT-qPCR and normalized to the housekeeping gene Rpl19; data were normalized to the vehicle-treated DM condition (n = 3). Bars represent mean values (± s.e.m.). Data were analyzed by two-way ANOVA (panels A and B) or one-way ANOVA (panel E) followed by post-hoc Holm–Sidak multiple comparison test; *P < 0.05, ***P < 0.001.

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    Fshb expression in primary pituitary cells is reduced by HDAC inhibition. Pituitaries from 8-week-old male mice were dispersed and cultured. After 2 days in culture, cells were treated with activin A (1 nmol/L), TSA (331 nmol/L), or both, for 6 h. mRNA levels of gonadotropin subunits (Fshb (A), Lhb (B), and Cga (C)) were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. Bars represent mean values (± s.e.m.) of n = 3 independent experiments. Activin A’s fold induction is indicated above the appropriate bars. Two-way ANOVA followed by a post-hoc Holm–Sidak multiple comparison test was used. *P < 0.05; **P < 0.01 when comparing activin A vs control; #P < 0.05; ###P < 0.001 when comparing TSA vs corresponding vehicle condition.

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    Class I, but not class II, HDAC inhibition suppresses Fshb expression in primary pituitary cultures. Pituitaries from 8-week-old male mice were dispersed and cultured. After 2 days in culture, cells were treated with TSA (45 nmol/L in (A, C and D)), entinostat (42.5 µmol/L in (A, C and D) or a range of concentrations in (B)), MC1568 (2.5 µmol/L in (A, C and D)), or SB431542 (1 or 10 µmol/L in (E)), in the presence or absence of activin A (1 nmol/L), for 6 h. mRNA levels of gonadotropin subunits (Fshb (A, B and E), Lhb (C), and Cga (D)) were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. Bars represent mean values (± s.e.m.) of n = 3 independent experiments, or n = 2 independent experiments for the dose-response curve in panel B. Activin A’s fold induction is indicated above the appropriate bars or data points. Data were analyzed by two-way ANOVA followed by a post-hoc Holm–Sidak multiple comparison test. ***P < 0.001 when comparing activin A vs control; ###P < 0.001 when comparing the inhibitor vs the corresponding vehicle condition.

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    HDAC inhibition impairs Hsd17b1 mRNA expression. LβT2 cells were treated for 6 h with activin A (1 nmol/L) in the presence or absence of TSA (331 nmol/L). Hsd17b1 mRNA levels were measured by RT-qPCR and normalized to the housekeeping gene Rpl19. Bars represent mean values (± s.e.m.) of n = 3 independent experiments. Data were analyzed by two-way ANOVA followed by post-hoc Holm–Sidak multiple comparison test. **P < 0.01 when comparing activin A vs control; #P < 0.05, ###P < 0.001 when comparing TSA vs corresponding vehicle condition.

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    HDAC inhibition does not block activin A-induced SMAD2 phosphorylation or nuclear import. (A) LβT2 cells were treated for 6 h with activin A (1 nmol/L) in the presence or absence of TSA (331 nmol/L). Total lysates were extracted and levels of phospho-SMAD2 and total SMAD2 were analyzed by western blot. A representative blot is shown. The data at the right represent the mean (± s.e.m.) of n = 4 independent experiments, and were analyzed by two-way ANOVA, followed by post-hoc Holm–Sidak multiple comparison test. *P < 0.05 when comparing activin A vs control. (B) A similar experiment was conducted, but nuclear and cytoplasmic protein fractions were prepared. Levels of pSMAD2, nucleoporin p62 (nuclear marker), and calnexin (cytoplasmic marker) were assessed by western blot. Both cytoplasmic and nuclear fractions were run on the same gel, and exposure times were the same between both compartments (intervening lanes were cropped for purposes of figure preparation). For protein quantification, phospho-SMAD2 levels were normalized to total SMAD2 levels, using the Bio-Rad QuantityOne software.

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    HDAC inhibition does not significantly affect SMAD3/4 signaling over short periods of time, and promotes it following longer incubation times. LβT2 cells were transfected with 225 ng of the CAGA-luc reporter plasmid, followed by treatment for 2, 6, or 24 h with (A) TSA (45 nmol/L), (B) MS-275 (42.5 μmol/L), (C) MC1568 (2.5 μmol/L), or (D) TMP269 (3.9 μmol/L) in the presence or absence of activin A (1 nmol/L). For each time point, values were normalized to the vehicle, control-treated condition. Bars represent mean values (± s.e.m.) of n = 4 independent experiments. Data were analyzed by two-way ANOVA followed by post-hoc Holm–Sidak multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001.

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    HDAC inhibition does not impair FOXL2 regulation of the porcine Fshb promoter. HEK293 cells were transfected with 225 ng of a porcine Fshb-promoter–luciferase reporter plasmid, along with 4.15 ng of an empty vector (pcDNA3.0) or a FOXL2 expression vector. Cells were treated for 6 h with TSA (45 nmol/L) in the presence or absence of activin A (1 nmol/L). Values were normalized to the vehicle, control-treated condition (empty vector). Bars represent mean values (± s.e.m.) of n = 3 independent experiments. Data were analyzed by two-way ANOVA followed by post-hoc Holm–Sidak multiple comparison test. *P < 0.05, **P < 0.01 when comparing treatments to the vehicle condition; #P < 0.05, ##P < 0.001 when comparing pcDNA3.0 and FOXL2 for a given treatment condition.

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