GATA3招募UTX抑制乳腺癌发生与转移的分子机制研究

GATA3 plays an important role as a transcription factor in maintaining epithelial cell stability and differentiation. UTX participates in transcriptional activation of target genes through its histone demethylase activity, which plays an important role in embryonic development and tumorigenesis. Our previous studies had shown that UTX is associated with the GATA family and has a similar expression profile to GATA3 in breast cancer cell lines, with a direct interaction. Therefore, to determine whether GATA3 could recruit UTX through epigenetic regulation to repress carcinogenesis and metastasis of breast cancer, need to be further studied. Based on the previous studies, we will further explore the interaction mechanism between GATA3 and UTX, analyze the genome-wide transcriptional targets of GATA3/UTX through RNA-seq and ChIP-seq. Further study will reveal the mechanism of GATA3/UTX in the development of breast cancer from the aspects of cell, mouse model and clinical data, providing a new target for the diagnosis and treatment of breast cancer.

GATA3作为转录因子在维持上皮细胞稳定性和分化状态中发挥重要作用。UTX可通过其组蛋白去甲基化酶活性转录激活基因的表达，从而在胚胎发育和肿瘤发生中发挥重要作用。我们的前期研究结果表明，UTX与GATA家族相关，并与GATA3在乳腺癌细胞系中表达谱相似，且有直接相互作用。然而，GATA3是否可以招募UTX通过表观遗传调控从而在乳腺癌发生发展中发挥作用的机制并不清楚，有待于进一步研究。本研究拟在前期研究的基础上，进一步探索GATA3与UTX之间的相互作用，经转录组测序和ChIP-seq寻找GATA3/UTX的可能共同调控的靶基因，揭示其生理病理学功能，进而利用小鼠模型和临床数据验证GATA3/UTX在乳腺癌发生发展中的作用机制，为乳腺癌的诊断和治疗提供新的靶点。

本项目通过使用分子生物学、细胞生物学、表观遗传学、动物实验技术，联合高通量测序、生物信息学等研究方法，系统地研究恶性肿瘤（尤其是乳腺癌）发生发展中关键因子GATA3、CUL4B、SIRT1等对肿瘤发生及转移的影响，揭示了恶性肿瘤（尤其是乳腺癌）的发生及转移过程中的关键通路及关键调控因子协同与拮抗的新机制（Advanced Science, 2021；Cell Death & Differentiation, 2022；山东大学学报（医学版），2022；中国生物化学与分子生物学报，2021）；并基于测序数据构建恶性肿瘤预后风险模型，筛选关键因子（Breast Cancer, 2022；Frontiers in Oncology, 2021；Aging-US, 2020；Cancer Cell International, 2020）；共发表SCI论文6篇，中文核心期刊论文2篇。此外，发表综述2篇，总结了肿瘤代谢、微生物微环境与表观遗传调控作用的进展（Frontiers in Oncology, 2022；Frontiers in Cell and Developmental Biology, 2021）。该项目的实施，为恶性肿瘤尤其是乳腺癌预警、诊断、治疗和药物筛选提供新思路、新途径和新靶标。以上成果均为在国家自然科学基金委青年项目的支持下获得，并已标注该基金。在该基金的支持下，项目负责人晋升副教授，培养博士研究生1名，硕士研究生1名。