Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology
Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology
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DOI：
10.1093/carcin/bgp324
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发表时间：
2010-03-01
期刊：
影响因子：
4.7
通讯作者：
Kirfel, Jutta
中科院分区：
文献类型：
--
作者：
Lim, Soyoung;Janzer, Andreas;Kirfel, Jutta
乳腺癌的发生是一个多步骤的过程，涉及遗传和表观遗传的变化。由于表观遗传变化如组蛋白修饰是潜在可逆的过程，因此人们一直致力于了解这种机制，目的是找到新的治疗方法以及更精确的乳腺癌诊断和预后工具。赖氨酸特异性脱甲基酶1（LSD1）通过去除组蛋白H3的甲基化赖氨酸4和赖氨酸9上的甲基而在基因表达调控中起关键作用。LSD 1对哺乳动物的发育至关重要，并参与许多生物学过程。考虑到最近的证据表明LSD 1参与了致癌作用，我们研究了LSD 1在乳腺癌中的作用。因此，我们开发了一种酶联免疫吸附测定法来测定乳腺癌组织标本中的LSD 1蛋白水平，并在雌激素受体（ER）阴性肿瘤中测定了非常高的LSD 1水平。药理学LSD 1抑制导致乳腺癌细胞的生长抑制。使用小干扰RNA方法敲低LSD 1诱导了几个增殖相关基因如p21、ERBB 2和CCNA 2的调节。此外，我们发现LSD1被募集到这些基因的启动子中。总之，我们的数据表明，LSD 1可以提供一个预测的侵略性生物学标记和一个新的有吸引力的治疗靶点，用于治疗ER阴性乳腺癌。
Breast carcinogenesis is a multistep process involving both genetic and epigenetic changes. Since epigenetic changes like histone modifications are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding novel therapies as well as more refined diagnostic and prognostic tools in breast cancer. Lysine-specific demethylase 1 (LSD1) plays a key role in the regulation of gene expression by removing the methyl groups from methylated lysine 4 of histone H3 and lysine 9 of histone H3. LSD1 is essential for mammalian development and involved in many biological processes. Considering recent evidence that LSD1 is involved in carcinogenesis, we investigated the role of LSD1 in breast cancer. Therefore, we developed an enzyme-linked immunosorbent assay to determine LSD1 protein levels in tissue specimens of breast cancer and measured very high LSD1 levels in estrogen receptor (ER)-negative tumors. Pharmacological LSD1 inhibition resulted in growth inhibition of breast cancer cells. Knockdown of LSD1 using small interfering RNA approach induced regulation of several proliferation-associated genes like p21, ERBB2 and CCNA2. Additionally, we found that LSD1 is recruited to the promoters of these genes. In summary, our data indicate that LSD1 may provide a predictive marker for aggressive biology and a novel attractive therapeutic target for treatment of ER-negative breast cancers.