UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer
UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer
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UHRF1 与散发性乳腺癌中 BRCA1 的表观遗传沉默相关
DOI：
10.1007/s10549-009-0652-2
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发表时间：
2010-09-01
影响因子：
3.8
通讯作者：
Shao, Zhi-ming
中科院分区：
文献类型：
--
作者：
Jin, Wei;Chen, Li;Shao, Zhi-ming
BRCA1与乳腺癌的发病机制密切相关，尽管缺乏突变，但散发性乳腺癌细胞中BRCA1 mRNA却减少。在本报告中，我们发现散发性乳腺癌中UHRF1（类泛素，包含PHD和RING指结构域1）的过度表达与DNA甲基化、脱乙酰化和组蛋白甲基化以及BRCA1启动子上抑制性转录复合物的募集密切相关。 UHRF1 的过度表达诱导组蛋白 H3 和 H4 的脱乙酰化，这是通过将组蛋白脱乙酰酶 1 (HDAC1) 招募到 BRCA1 启动子来促进的。乙酰化的丧失伴随着关键转录因子 MyoD、CBP 和 p300 结合的丧失。 UHRF1 还将组蛋白赖氨酸甲基转移酶 G9a 招募到 BRCA1 启动子，组蛋白 3 赖氨酸 4 (H3K4) 被去甲基化，组蛋白 3 赖氨酸 9 (H3K9) 被甲基化。最后，UHRF1 的过度表达通过将 DNMT1 募集至 BRCA1 启动子而导致 BRCA1 启动子甲基化，从而锁定 BRCA1 的显着抑制。首次描述UHRF1通过诱导DNA甲基化、组蛋白修饰以及在BRCA1启动子上募集转录复合物来调节BRCA1转录，UHRF1是散发性乳腺癌的新生物标志物。
BRCA1is closely related to the pathogenesis of breast cancer,BRCA1mRNA is reduced in sporadic breast cancer cells despite the lack of mutations. In the present report, we found that overexpression of UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) was closely related to DNA methylation, deacetylation, and methylation of histones, recruitment of an inhibiting transcriptional complex on theBRCA1promoter in sporadic breast cancer. Overexpression of UHRF1 induced deacetylation of histones H3 and H4, which was facilitated by recruitment of histone deacetylase1 (HDAC1) to theBRCA1promoter. Loss of acetylation was accompanied by loss of binding of the key transcription factors MyoD, CBP, and p300. UHRF1 also recruited histone lysine methyltransferase G9a to theBRCA1promoter and histone 3 lysine 4 (H3K4) was demethylated, and histone 3 lysine 9 (H3K9) was methylated. Finally, overexpression of UHRF1 leaded to methylation ofBRCA1promoter by recruitment of DNMT1 to theBRCA1promoter, locking in marked suppression ofBRCA1. It is the first to describe that UHRF1 is responsible for regulatingBRCA1transcription by inducing DNA methylation, histone modifications, and recruitment of transcriptional complex on theBRCA1promoter, UHRF1 is a new bio-marker in sporadic breast cancer.