Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer
Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer
复制标题
LSD1 Ser112 的磷酸化对其诱导乳腺癌 EMT 和转移的功能至关重要
DOI：
10.1007/s10549-016-3959-9
复制
发表时间：
2016-10-01
影响因子：
3.8
通讯作者：
Zhang, Yu
中科院分区：
文献类型：
--
作者：
Feng, Jingxin;Xu, Guiying;Zhang, Yu
目的LSD 1在包括乳腺癌在内的多种肿瘤中过表达，但其在肿瘤发生中的作用尚不完全清楚。本研究旨在揭示LSD 1在乳腺癌发生发展中的作用。此外，有报道称LSD 1的丝氨酸112残基被PKCα磷酸化对其基因调控功能至关重要。我们还探讨了这种磷酸化是否会影响LSD 1的作用，在乳腺癌development.MethodsThis研究包括LSD 1 IHC数据产生的163例乳腺癌样本和72例正常组织的组织微阵列。在体外，评估LSD 1、LSD 1 S112 D突变体（磷酸化模拟）和LSD 1 S112 A突变体（非磷酸化模拟）在诱导EMT中的作用。机制上，我们检查了LSD 1及其突变体对E-钙粘蛋白启动子组蛋白修饰的作用。我们还研究了LSD 1及其突变体在裸鼠转移模型中的作用，结果我们发现LSD 1在乳腺癌组织中的表达水平高于正常组织，并且LSD 1的表达与乳腺癌转移密切相关。LSD 1通过去甲基化H3 K4 me抑制E-cadherin的表达而增强乳腺上皮细胞的EMT，在此过程中，LSD 1 Ser 112的磷酸化对其结合和去甲基化活性至关重要。在体内，LSD 1的敲低削弱了裸鼠中MDA-MB-231乳腺癌细胞的转移能力。异位过表达的LSD 1或LSD 1 S112 D突变体（磷酸化模拟）有利于转移，而LSD 1 S112 A突变体（一个unphosphorylation模拟）未能影响transferation.ConclusionsData在这份报告中指出，LSD 1是能够诱导EMT和促进乳腺癌转移，和磷酸化LSD 1 Ser 112是至关重要的这些功能。
PurposeLSD1 is overexpressed in various cancers including breast cancer, but its functional roles in tumourigenesis are not fully understood. This study aims at revealing the role of LSD1 in breast cancer development. In addition, it has been reported that phosphorylation of the Serine 112 residue of LSD1 by PKCα is crucial for its function in gene regulation. We also explored whether this phosphorylation affects LSD1’s role in breast cancer development.MethodsThis study includes LSD1 IHC data generated with tissue microarrays of 163 cases of breast cancer samples and 72 normal tissues. In vitro, role of LSD1, LSD1 S112D mutant (a phosphorylation simulation) and LSD1 S112A mutant (an unphosphorylation simulation) in induction of EMT is evaluated. Mechanismly, we checked the role of LSD1 and its mutant on E-cadherin promoter histone modifications. We also investigated the role of LSD1 and its mutants in metastasis with a nude mice model.ResultsWe found LSD1 is expressed at a higher level in breast cancer tissues compared with that in normal tissues, and LSD1 expression is closely linked to breast cancer metastasis. LSD1 potentiates EMT in breast epithelia cells by repressing E-cadherin expression through demethylating H3K4me at gene’s promoter, during which phosphorylation of LSD1 Ser112 is crucial for its binding and demethylation activity. In vivo, knockdown of LSD1 impairs the metastatic ability of MDA-MB-231 breast cancer cells in nude mice. Ectopic overexpression of either LSD1 or LSD1 S112D mutant (a phosphorylation simulation) facilitates metastasis, whereas the LSD1 S112A mutant (an unphosphorylation simulation) fails to affect the metastasis.ConclusionsData presented in this report indicate that LSD1 is able to induce EMT and to promote metastasis in breast cancer, and phosphorylation at LSD1 Ser112 is crucial for these functions.