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Liver x receptors protect from development of prostatic intra-epithelial neoplasia in mice.

Pommier AJ, Dufour J, Alves G, Viennois E, De Boussac H, Trousson A, Volle DH, Caira F, Val P, Arnaud P, Lobaccaro JM, Baron S - PLoS Genet. (2013)

Bottom Line: LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux.Elevation of circulating cholesterol in Lxrαβ-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia.This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions.

View Article: PubMed Central - PubMed

Affiliation: Clermont Université, Université Blaise Pascal, Génétique Reproduction et Développement, BP 10448 Clermont-Ferrand, France.

ABSTRACT
LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαβ-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.

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High-cholesterol diet induces proliferation in LXR mutant mouse prostate.(A) Histological sections of dorsal prostate lobes of 5 month-old WT (a,b,c,d) and LXR  mice (e,f,g,h) fed normal or high cholesterol diet were analyzed after H&E staining (Left) or Ki67 IHC (Right). Arrowheads point Ki67-positive cells. Higher magnification of the prostatic epithelium of LXR  mice fed a high cholesterol diet revealed abnormal features (i). Arrowheads indicate atypical cells with enlarged nuclei and prominent nucleoli which represent typical signs of PIN. Ep: Epithelium, St: Stroma (Scale bars = 50 µm). (B) IHC for Ki67 was quantified by counting the percentage of prostatic acini with proliferative cells and the average Ki67+ cell number in proliferative acini (N = 6 per group). (C) qPCR analysis of CyclinD1 and CyclinD2 expression (N = 9/13 per group). * p<0.05, ** p<0.01, *** p<0.001 in Student's t test. Error bars represent the ± mean SEM.
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pgen-1003483-g001: High-cholesterol diet induces proliferation in LXR mutant mouse prostate.(A) Histological sections of dorsal prostate lobes of 5 month-old WT (a,b,c,d) and LXR mice (e,f,g,h) fed normal or high cholesterol diet were analyzed after H&E staining (Left) or Ki67 IHC (Right). Arrowheads point Ki67-positive cells. Higher magnification of the prostatic epithelium of LXR mice fed a high cholesterol diet revealed abnormal features (i). Arrowheads indicate atypical cells with enlarged nuclei and prominent nucleoli which represent typical signs of PIN. Ep: Epithelium, St: Stroma (Scale bars = 50 µm). (B) IHC for Ki67 was quantified by counting the percentage of prostatic acini with proliferative cells and the average Ki67+ cell number in proliferative acini (N = 6 per group). (C) qPCR analysis of CyclinD1 and CyclinD2 expression (N = 9/13 per group). * p<0.05, ** p<0.01, *** p<0.001 in Student's t test. Error bars represent the ± mean SEM.

Mentions: Under a standard diet, dorsolateral prostates of Lxrαβ-/- double knockout mice (Lxr-/-) were histologically indistinguishable from their wild-type (WT) counterparts, as shown by H&E staining (Figure 1Aa and e) and Ki67 IHC (Figure 1Ab and f). In order to increase circulating cholesterol levels, WT and knockout mice were fed a standard or a hypercholesterolemic diet, as previously described [11], [12]. This cholesterol surge had no effect on the gross histology of WT dorsolateral prostates (Figure 1Ac). In contrast, analysis of LXR mutant prostates revealed a disorganization of the epithelial layer, which was reminiscent of PIN grade II [13] (Figure 1Ag), characterized by the formation of cribriform and tufting patterns. Nuclei were enlarged and displayed prominent nucleoli (Figure 1Ai). The PIN status of the lesions was confirmed by an increased proliferation as demonstrated by Ki67 staining (Figure 1Ah, 1B) and Cyclin D1 and D2 overexpression (Figure 1C). The PIN phenotype was restricted to the dorsolateral prostate (Figure S1A, S1B) and was dependent on the ablation of both Lxrα and Lxrβ. Indeed, single knockout prostates were comparable with WT glands in terms of histology and proliferation (Figure S1C, S1D).


Liver x receptors protect from development of prostatic intra-epithelial neoplasia in mice.

Pommier AJ, Dufour J, Alves G, Viennois E, De Boussac H, Trousson A, Volle DH, Caira F, Val P, Arnaud P, Lobaccaro JM, Baron S - PLoS Genet. (2013)

High-cholesterol diet induces proliferation in LXR mutant mouse prostate.(A) Histological sections of dorsal prostate lobes of 5 month-old WT (a,b,c,d) and LXR  mice (e,f,g,h) fed normal or high cholesterol diet were analyzed after H&E staining (Left) or Ki67 IHC (Right). Arrowheads point Ki67-positive cells. Higher magnification of the prostatic epithelium of LXR  mice fed a high cholesterol diet revealed abnormal features (i). Arrowheads indicate atypical cells with enlarged nuclei and prominent nucleoli which represent typical signs of PIN. Ep: Epithelium, St: Stroma (Scale bars = 50 µm). (B) IHC for Ki67 was quantified by counting the percentage of prostatic acini with proliferative cells and the average Ki67+ cell number in proliferative acini (N = 6 per group). (C) qPCR analysis of CyclinD1 and CyclinD2 expression (N = 9/13 per group). * p<0.05, ** p<0.01, *** p<0.001 in Student's t test. Error bars represent the ± mean SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3649972&req=5

pgen-1003483-g001: High-cholesterol diet induces proliferation in LXR mutant mouse prostate.(A) Histological sections of dorsal prostate lobes of 5 month-old WT (a,b,c,d) and LXR mice (e,f,g,h) fed normal or high cholesterol diet were analyzed after H&E staining (Left) or Ki67 IHC (Right). Arrowheads point Ki67-positive cells. Higher magnification of the prostatic epithelium of LXR mice fed a high cholesterol diet revealed abnormal features (i). Arrowheads indicate atypical cells with enlarged nuclei and prominent nucleoli which represent typical signs of PIN. Ep: Epithelium, St: Stroma (Scale bars = 50 µm). (B) IHC for Ki67 was quantified by counting the percentage of prostatic acini with proliferative cells and the average Ki67+ cell number in proliferative acini (N = 6 per group). (C) qPCR analysis of CyclinD1 and CyclinD2 expression (N = 9/13 per group). * p<0.05, ** p<0.01, *** p<0.001 in Student's t test. Error bars represent the ± mean SEM.
Mentions: Under a standard diet, dorsolateral prostates of Lxrαβ-/- double knockout mice (Lxr-/-) were histologically indistinguishable from their wild-type (WT) counterparts, as shown by H&E staining (Figure 1Aa and e) and Ki67 IHC (Figure 1Ab and f). In order to increase circulating cholesterol levels, WT and knockout mice were fed a standard or a hypercholesterolemic diet, as previously described [11], [12]. This cholesterol surge had no effect on the gross histology of WT dorsolateral prostates (Figure 1Ac). In contrast, analysis of LXR mutant prostates revealed a disorganization of the epithelial layer, which was reminiscent of PIN grade II [13] (Figure 1Ag), characterized by the formation of cribriform and tufting patterns. Nuclei were enlarged and displayed prominent nucleoli (Figure 1Ai). The PIN status of the lesions was confirmed by an increased proliferation as demonstrated by Ki67 staining (Figure 1Ah, 1B) and Cyclin D1 and D2 overexpression (Figure 1C). The PIN phenotype was restricted to the dorsolateral prostate (Figure S1A, S1B) and was dependent on the ablation of both Lxrα and Lxrβ. Indeed, single knockout prostates were comparable with WT glands in terms of histology and proliferation (Figure S1C, S1D).

Bottom Line: LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux.Elevation of circulating cholesterol in Lxrαβ-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia.This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions.

View Article: PubMed Central - PubMed

Affiliation: Clermont Université, Université Blaise Pascal, Génétique Reproduction et Développement, BP 10448 Clermont-Ferrand, France.

ABSTRACT
LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαβ-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.

Show MeSH
Related in: MedlinePlus