Aurora-A激酶核转移促进SIRT1对CDKN2A表达的抑制作用并增强乳腺癌干细胞干性的机制研究

Relapse and chemoresistance are the major obstacles faced in clinical treatment of breast cancer. The breast cancer stem cells are the primary causes of cancer relapse and chemoresistance. Our published study shows that nuclear Aurora-A (AurA) functions as a transcriptional regulation factor in a kinase activity independent manner to activate MYC transcription and enhance the breast cancer stem cell phenotype. Our study indicates that inhibition of nuclear AurA function could be a promising strategy to targeting breast cancer stem cells. However, how nuclear AurA control genes expression to enhance the breast cancer stem cell phenotype is still unclear. Our recently study shows that AurA interacts with histone deacetylase SIRT1. Down-regulation of AurA decreases the interaction between SIRT1 and histone H3. Moreover, up-regulation of AurA and SIRT1 suppress the expression of CDKN2A. We also find that both of suppressing SIRT1 expression and increasing CDKN2A expression decrease the population of breast cancer stem cells. These data indicate that AurA-SIRT1-CDKN2A axis could be critical for the breast cancer stem cell phenotype. Thus, our future works need to establish the functional link between AurA-SIRT1-CDKN2A axis and breast cancer stem cell phenotype. Furthermore, we need to reveal the mechanism of how AurA regulates SIRT1 function and the expression of CDKN2A to control the breast cancer stem cell phenotype. Finally, we need to verify the correlation between AurA-SIRT1-CDKN2A axis and the breast cancer stem cell phenotype in animal model and clinical breast cancer samples. By conducting the study of this project, our findings may provide a rationale to develop strategies to target the nuclear oncogenic function of AurA and breast cancer stem cells.

乳腺癌干细胞(BCSC)是乳腺癌复发、耐药，并导致治疗失败的根源。前期研究表明Aurora-A(AurA)在细胞癌变时发生核转移，进而以非激酶活性依赖的转录调控功能促进BCSC干性(Nat Commun,2016)。但AurA核转移发挥转录调控功能并促进BCSC干性的机制尚不清楚。本项目前期研究发现SIRT1是AurA的互做蛋白，下调AurA抑制SIRT1与Histone-H3结合，我们还发现AurA与SIRT1均能抑制CDKN2A表达，下调SIRT1或过表达CDKN2A能降低BCSC比例。本项目拟明确AurA-SIRT1-CDKN2A在BCSC中的关键调控作用，阐明AurA调控SIRT1功能及CDKN2A表达的分子机制，并在动物实验及临床样本中验证AurA-SIRT1-CDKN2A对BCSC干性的关键调控作用。本研究将为靶向AurA核内转录调控功能、抑制BCSC提供理论依据。

乳腺癌干细胞(BCSC)是乳腺癌复发、耐药，并导致治疗失败的根源。前期研究表明Aurora-A(AurA)在细胞癌变时发生核转移，以非激酶活性依赖的转录调控功能促进BCSC干性。但AurA核转移发挥转录调控功能并促进BCSC干性的机制尚不清楚。本项目拟明确AurA-SIRT1-CDKN2A在BCSC中的关键调控作用，阐明AurA调控SIRT1功能及CDKN2A表达的分子机制，并在动物实验及临床样本中验证AurA-SIRT1-CDKN2A对BCSC干性的关键调控作用。目前本项目已获得以下成果：1. 明确了核内Aurora-A 激酶、SIRT1 和CDKN2A 在乳腺癌干细胞干性调控中的作用及相互关系；2. 揭示核内Aurora-A 激酶通过表观遗传学的机制调控基因转录，SIRT1是介导核内Aurora-A 激酶这一功能的关键分子；3. 初步明确核内Aurora-A 激酶、SIRT1、CDKN2A 以及乙酰化Histone(H1、H3 或H4)表达与乳腺癌分期、转移、复发、生存等的相关性；4. 项目执行期间发表SCI论文3篇，分别在Cancer Cell International（影响因子3.439，本项目标注第一，通讯作者）、BMB Reports（影响因子2.966，本项目标注第一，通讯作者/第一作者）和Scientific Reports（影响因子4.011，本项目标注第三，共同第一，排名第三）发表。项目研究期间参与培养博士生4名。预期本研究将为靶向AurA核内转录调控功能、抑制BCSC提供理论依据。