SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer.
SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer.
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DOI：
10.1158/0008-5472.can-11-1446
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发表时间：
2011-11-01
期刊：
影响因子：
11.2
通讯作者：
Thangaraju M
中科院分区：
文献类型：
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作者：
Elangovan S;Ramachandran S;Venkatesan N;Ananth S;Gnana-Prakasam JP;Martin PM;Browning DD;Schoenlein PV;Prasad PD;Ganapathy V;Thangaraju M
NAD 依赖性组蛋白脱乙酰酶 SIRT1 在许多人类癌症中过度表达并被催化激活，但最近的研究表明，它实际上可能在体内充当肿瘤抑制因子和转移抑制剂。在乳腺癌中，SIRT1 稳定被认为有助于雌激素受体 α (ERα) 的致癌潜力，但 SIRT1 活性也与 ERα 脱乙酰化和失活有关。在这项研究中，我们证明 SIRT1 对于雌激素促进乳腺癌至关重要。 ERα 在乳腺癌细胞中与 SIRT1 发生物理相互作用和功能协作。 ERα 还与 SIRT1 的启动子结合并增加其转录。 ERα 诱导的 SIRT1 表达足以激活乳腺癌细胞中的抗氧化和促生存基因，例如过氧化氢酶和谷胱甘肽过氧化物酶，并灭活肿瘤抑制基因，例如细胞周期蛋白 G2 (CCNG2) 和 p53。此外，SIRT1失活消除了雌激素/ERα诱导的细胞生长和肿瘤发展，引发细胞凋亡。总而言之，这些结果表明 SIRT1 是雌激素诱导的乳腺癌生长所必需的。我们的研究结果表明，SIRT1 抑制剂和抗雌激素化合物的组合可能为乳腺癌提供更有效的治疗策略。
The NAD-dependent histone deacetylase SIRT1 is overexpressed and catalytically activated in a number of human cancers, but recent studies argue have actually suggested that it may function as a tumor suppressor and metastasis inhibitor in vivo. In breast cancer, SIRT1 stabilization has been suggested to contribute to the oncogenic potential of the estrogen receptor α (ERα), but SIRT1 activity has also been associated with ERα deacetylation and inactivation. In this study, we show that SIRT1 is critical for estrogen to promote breast cancer. ERα physically interacted and functionally cooperated with SIRT1 in breast cancer cells. ERα also bound to the promoter for SIRT1 and increased its transcription. SIRT1 expression induced by ERα was sufficient to activate anti-oxidant and pro-survival genes in breast cancer cells, such as catalase and glutathione peroxidase, and to inactivate tumor suppressor genes such as cyclin G2 (CCNG2) and p53. Moreover, SIRT1 inactivation eliminated estrogen/ERα-induced cell growth and tumor development, triggering apoptosis. Taken together, these results indicated that SIRT1 is required for estrogen-induced breast cancer growth. Our findings imply that the combination of SIRT1 inhibitors and anti-estrogen compounds may offer more effective treatment strategies for breast cancer.