TWIST represses estrogen receptor-alpha expression by recruiting the NuRD protein complex in breast cancer cells.
TWIST represses estrogen receptor-alpha expression by recruiting the NuRD protein complex in breast cancer cells.
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TWIST 通过在乳腺癌细胞中募集 NuRD 蛋白复合物来抑制雌激素受体 α 的表达。
DOI：
10.7150/ijbs.4164
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发表时间：
2012
影响因子：
9.2
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Fu J;Zhang L;He T;Xiao X;Liu X;Wang L;Yang L;Yang M;Zhang T;Chen R;Xu J
乳腺肿瘤中雌激素受体α(ERα)的表达缺失和Twist1的表达增强与肿瘤复发转移增加和无瘤生存不良有关。然而，TWIST和ERα之间的分子和功能调控关系尚不清楚。在这项研究中，我们发现TWIST与编码ERα的人ESR1基因内含子7的染色质区域相关。这种TWIST的关联有效地将核小体重塑和去乙酰酶(NuRD)抑制物复合体招募到该区域，从而减少了组蛋白H3K9的乙酰化，增加了组蛋白H3K9的甲基化，并抑制了ESR1的表达。与这些分子事件相一致的是，在乳腺癌细胞系和人乳腺导管癌中，TWIST的表达与ERα的表达呈负相关。在TWIST阴性和ERα阳性的乳腺癌细胞如T47D和MCF-7中强制表达TWIST会降低ERα的表达，而在TWIST阳性和ERα阴性的乳腺癌细胞如MDAMB-435和4T1细胞中TWIST的敲除会增加ERα的表达。此外，抑制组蛋白脱乙酰酶活性，包括NuRD复合体中的组蛋白脱乙酰酶活性，显著增加了mda-MB-435和4T1细胞中ERα的表达。HDAC抑制和twist基因敲除不能进一步增加4T1和MDAMB-435细胞ERα的表达。这些结果表明TWIST/NURD抑制乳腺癌细胞ERα的表达。因此，TWIST可能成为将ERα阴性乳腺癌转化为ERα阳性乳腺癌的潜在分子靶点，使这些癌症能够恢复对选择性ERα拮抗剂如他莫昔芬和雷洛昔芬内分泌治疗的敏感性。
Loss of estrogen receptor α (ERα) expression and gain of TWIST (TWIST1) expression in breast tumors correlate with increased disease recurrence and metastasis and poor disease-free survival. However, the molecular and functional regulatory relationship between TWIST and ERα are unclear. In this study, we found TWIST was associated with a chromatin region in intron 7 of the human ESR1 gene coding for ERα. This association of TWIST efficiently recruited the nucleosome remodeling and deacetylase (NuRD) repressor complex to this region, which subsequently decreased histone H3K9 acetylation, increased histone H3K9 methylation and repressed ESR1 expression in breast cancer cells. In agreement with these molecular events, TWIST expression was inversely correlated with ERα expression in both breast cancer cell lines and human breast ductal carcinomas. Forced expression of TWIST in TWIST-negative and ERα-positive breast cancer cells such as T47D and MCF-7 cells reduced ERα expression, while knockdown of TWIST in TWIST-positive and ERα-negative breast cancer cells such as MDA-MB-435 and 4T1 cells increased ERα expression. Furthermore, inhibition of histone deacetylase (HDAC) activity including the one in NuRD complex significantly increased ERα expression in MDA-MB-435 and 4T1 cells. HDAC inhibition together with TWIST knockdown did not further increase ERα expression in 4T1 and MDA-MB-435 cells. These results demonstrate that TWIST/NuRD represses ERα expression in breast cancer cells. Therefore, TWIST may serve as a potential molecular target for converting ERα-negative breast cancers to ERα-positive breast cancers, allowing these cancers to restore their sensitivity to endocrine therapy with selective ERα antagonists such as tamoxifen and raloxifene.
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