Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer.
Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer.
复制标题
DOI：
10.1186/bcr3229
复制
发表时间：
2012-07-19
期刊：
影响因子：
--
通讯作者：
Vadlamudi RK
中科院分区：
文献类型：
--
作者：
Cortez V;Mann M;Tekmal S;Suzuki T;Miyata N;Rodriguez-Aguayo C;Lopez-Berestein G;Sood AK;Vadlamudi RK
雌激素受体（ER）辅助调节因子脯氨酸谷氨酸和富含亮氨酸的蛋白1（PELP 1）是一种原癌基因，通过与赖氨酸特异性组蛋白脱甲基酶1（KDM 1）的相互作用调节ER靶基因启动子上的表观遗传变化。在这项研究中，我们使用临床前模型评估了使用脂质体（1，2-二油酰基-sn-甘油-3-磷脂酰胆碱; DOPC）siRNA下调PELP 1表达和KDM 1抑制剂帕吉林和N-（（1 S）-3-（3-（反式-2-氨基环丙基）苯氧基）-1-（苄基氨基甲酰基）丙基）苯甲酰胺体内靶向PELP 1-KDM 1轴的治疗潜力。临床前异种移植模型用于测试药物在体内的功效。对肿瘤组织进行Ki-67和末端脱氧核苷酸转移酶dUTP缺口末端标记免疫组织化学分析。采用细胞增殖、报告基因、染色质免疫沉淀和实时荧光定量RT-PCR检测PELP 1-KDM轴阻断剂的体外作用。使用治疗抗性模型细胞测试KDM 1靶向药物单独或与来曲唑和他莫昔芬组合的功效。用PELP 1-siRNA-DOPC或帕吉林治疗ER阳性异种移植物乳腺肿瘤分别使肿瘤体积减少58.6%和62%。在绝经后模型中，肿瘤生长仅由局部雌激素合成刺激，每日帕吉林治疗可使肿瘤体积减少78%。切除的肿瘤的免疫组织化学分析显示，细胞增殖，诱导凋亡和抑制性表观遗传修饰的上调相结合的减少。体外药理学抑制KDM 1增加了ER靶基因启动子上组蛋白H3在赖氨酸9（H3 K9 me 2）处的抑制性组蛋白标记二甲基化，并减少了组蛋白激活标记H3 K9（H3 K9 Ac）的乙酰化。将KDM 1靶向药物与目前的内分泌疗法相结合，大大阻碍了耐药乳腺癌细胞的生长，并恢复了其对治疗的敏感性。我们的研究结果表明，抑制PELP 1-KDM 1介导的组蛋白修饰是一种潜在的治疗策略，可阻断乳腺癌进展和治疗耐药性。
The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models. Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells. Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment. Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.
登录
查看更多内容
影响因子：
64.5
作者：
Garcia-Bassets, Ivan;Kwon, Young-Soo;Rosenfeld, Michael G.
通讯作者：
Rosenfeld, Michael G.
影响因子：
8
作者：
Nabha, SM;Glaros, S;Reddy, KB
通讯作者：
Reddy, KB
影响因子：
11.2
作者：
Nair, SS;Mishra, SK;Vadlamudi, RK
通讯作者：
Vadlamudi, RK
影响因子：
6.2
作者：
Macedo, Luciana F.;Sabnis, Gauri;Brodie, Angela
通讯作者：
Brodie, Angela
影响因子：
3.8
作者：
Habashy, Hany Onsy;Powe, Desmond G.;Ellis, Ian O.
通讯作者：
Ellis, Ian O.