Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells.
Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells.
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DOI：
10.1007/s10549-011-1480-8
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发表时间：
2012-02
影响因子：
3.8
通讯作者：
Davidson, Nancy E.
中科院分区：
文献类型：
--
作者：
Huang, Yi;Vasilatos, Shauna N.;Boric, Lamia;Shaw, Patrick G.;Davidson, Nancy E.
组蛋白赖氨酸脱甲基酶（KDM）和赖氨酸脱乙酰酶（HDAC）的异常活性与乳腺癌发生中的异常基因表达相关。然而，在染色质重塑和基因转录调控中KDM和HDAC之间的串扰的精确分子机制仍然是难以捉摸的。在这项研究中，我们发现，用靶向锌辅因子依赖性I/II类HDAC而不是NAD+依赖性III类HDAC的抑制剂治疗人乳腺癌细胞，导致H3 K4 me 2显著增加，H3 K4 me 2是组蛋白赖氨酸特异性去甲基化酶1（LSD 1）的特异性底物，也是促进转录激活的关键染色质标记。我们还证明了通过药理学抑制剂帕吉林或siRNA抑制LSD 1活性导致H3 K9（AcH 3 K9）的乙酰化增加。然而，siRNA敲除LSD 1的同源物LSD 2未能改变AcH 3 K9的水平，这表明LSD 2活性可能与HDAC活性在功能上无关。LSD 1和HDAC抑制剂的联合治疗导致H3 K4 me 2和AcH 3 K9水平的提高，并表现出对乳腺癌细胞的协同生长抑制。最后，微阵列筛选确定了一个独特的基因子集，其表达显着改变的LSD 1和HDAC抑制剂的组合治疗。我们的研究表明，LSD 1密切相互作用与组蛋白去乙酰化酶在人类乳腺癌细胞。抑制组蛋白去甲基化和去乙酰化在调节基因表达和生长抑制方面表现出协同作用，可能代表乳腺癌表观遗传治疗的一种有前途的新方法。
Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are associated with aberrant gene expression in breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD+ dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacological inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer.
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影响因子：
64.8
作者：
Lee, MG;Wynder, C;Shiekhattar, R
通讯作者：
Shiekhattar, R
影响因子：
4.8
作者：
Liang, Genqing;Bansal, Geetanjali;Druey, Kirk M.
通讯作者：
Druey, Kirk M.
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
4.7
作者：
Bradley, Chastity;van der Meer, Riet;Parl, Fritz F.
通讯作者：
Parl, Fritz F.
影响因子：
5.7
作者：
Rao, Rekha;Nalluri, Srilatha;Bhalla, Kapil N.
通讯作者：
Bhalla, Kapil N.