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肝 X 受体可预防小鼠前列腺上皮内瘤的发生。

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

机构信息

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

出版信息

PLoS Genet. 2013 May;9(5):e1003483. doi: 10.1371/journal.pgen.1003483. Epub 2013 May 9.

DOI:10.1371/journal.pgen.1003483
PMID:23675307
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3649972/
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.

摘要

LXR（肝 X 受体）作为“传感器”蛋白，调节胆固醇的摄取、储存和外排。已知 LXR 信号通路影响包括人前列腺癌细胞系在内的不同细胞类型的增殖。本研究表明，高脂饮食喂养的 LXR 基因敲除小鼠中 LXR 的缺失可重现前列腺癌发展的初始步骤。Lxrαβ-/- 双基因敲除小鼠循环胆固醇水平升高导致胆固醇酯蓄积和前列腺上皮内瘤形成。这种表型与组蛋白甲基转移酶 EZH2（ Enhancer of Zeste Homolog 2）的表达增加有关，通过组蛋白 H3（H3）赖氨酸 27 上的赖氨酸 27 甲基化（H3K27）增加，导致肿瘤抑制因子 Msmb 和 Nkx3.1 的表达下调。总之，我们的数据提供了 LXR、胆固醇稳态和肿瘤抑制基因表达的表观遗传控制之间的新联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/3da87db1c7bc/pgen.1003483.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/f18888f84aa7/pgen.1003483.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/a91695077a33/pgen.1003483.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/ceaece6ef63d/pgen.1003483.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/c4db3ccb4c95/pgen.1003483.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/0ad25b2140f7/pgen.1003483.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/3da87db1c7bc/pgen.1003483.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/f18888f84aa7/pgen.1003483.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/a91695077a33/pgen.1003483.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/ceaece6ef63d/pgen.1003483.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/c4db3ccb4c95/pgen.1003483.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/0ad25b2140f7/pgen.1003483.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f55/3649972/3da87db1c7bc/pgen.1003483.g006.jpg

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