Cancer Center, Faculty of Health Sciences, University of Macau, Macau, Macau SAR, China.
Ministry of Education (MOE) Frontier Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
Front Immunol. 2022 Apr 25;13:861221. doi: 10.3389/fimmu.2022.861221. eCollection 2022.
Epigenetic reprogramming is an independent mode of gene expression that often involves changes in the transcription and chromatin structure due to tumor initiation and development. In this study, we developed a specifically modified peptide array and searched for a recognized epigenetic reader. Our results demonstrated that BRD4 is not only an acetylation reader but of propionylation as well. We also studied the quantitative binding affinities between modified peptides and epigenetic regulators by isothermal titration calorimetry (ITC). Furthermore, we introduced the Fgfr2-S252W transgenic mouse model to confirm that this acetylation is associated with the activation of c-Myc and drives tumor formation. Targeted disruption of BRD4 in Fgfr2-S252W mouse tumor cells also confirmed that BRD4 is a key regulator of histone 3 acetylation. Finally, we developed a tumor slice culture system and demonstrated the synergy between immune checkpoint blockade and targeted therapy in triple-negative breast cancer (TNBC). These data extend our understanding of epigenetic reprogramming and epigenetics-based therapies.
表观遗传重编程是一种独立的基因表达模式，由于肿瘤的发生和发展，通常涉及转录和染色质结构的变化。在这项研究中，我们开发了一种经过特殊修饰的肽阵列，并寻找公认的表观遗传阅读器。我们的结果表明，BRD4 不仅是乙酰化阅读器，也是丙酰化阅读器。我们还通过等温滴定量热法（ITC）研究了修饰肽和表观遗传调节剂之间的定量结合亲和力。此外，我们引入了 Fgfr2-S252W 转基因小鼠模型，以证实这种乙酰化与 c-Myc 的激活有关，并驱动肿瘤形成。靶向敲除 Fgfr2-S252W 小鼠肿瘤细胞中的 BRD4 也证实 BRD4 是组蛋白 3 乙酰化的关键调节剂。最后，我们开发了肿瘤切片培养系统，并证明了免疫检查点阻断和针对三阴性乳腺癌（TNBC）的靶向治疗之间的协同作用。这些数据扩展了我们对表观遗传重编程和基于表观遗传学的治疗的理解。
