Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy.
IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy.
Sci Rep. 2023 Aug 7;13(1):12749. doi: 10.1038/s41598-023-38685-7.
Epigenetic dysregulation of chromatin is one of the hallmarks of cancer development and progression, and it is continuously investigated as a potential general bio-marker of this complex disease. One of the nuclear factors involved in gene regulation is the unique DEK protein-a histone chaperon modulating chromatin topology. DEK expression levels increase significantly from normal to cancer cells, hence raising the possibility of using DEK as a tumor marker. Although DEK is known to be implicated in epigenetic and transcriptional regulation, the details of these interactions and their relevance in cancer development remain largely elusive. In this work, we investigated the spatial correlation between the nuclear distribution of DEK and chromatin patterns-alongside breast cancer progression-leveraging image cross-correlation spectroscopy (ICCS) coupled with Proximity Ligation Assay (PLA) analysis. We performed our study on the model based on three well-established human breast cell lines to consider this tumor's heterogeneity (MCF10A, MCF7, and MDA-MB-231 cells). Our results show that overexpression of DEK correlates with the overall higher level of spatial proximity between DEK and histone marks corresponding to gene promoters regions (H3K9ac, H3K4me3), although it does not correlate with spatial proximity between DEK and gene enhancers (H3K27ac). Additionally, we observed that colocalizing fractions of DEK and histone marks are lower for the non-invasive cell subtype than for the highly invasive cell line (MDA-MB-231). Thus, this study suggests that the role of DEK on transcriptionally active chromatin regions varies depending on the subtype of the breast cancer cell line.
染色质的表观遗传失调是癌症发展和进展的标志之一，作为这种复杂疾病的潜在通用生物标志物，它一直在被不断研究。参与基因调控的核因子之一是独特的 DEK 蛋白——一种调节染色质拓扑结构的组蛋白伴侣。DEK 的表达水平从正常细胞到癌细胞显著增加，因此有可能将 DEK 用作肿瘤标志物。尽管已知 DEK 参与表观遗传和转录调控，但这些相互作用的细节及其在癌症发展中的相关性在很大程度上仍未被揭示。在这项工作中，我们利用图像互相关光谱学（ICCS）结合邻近连接分析（PLA）分析，研究了 DEK 的核分布与沿着乳腺癌进展的染色质模式之间的空间相关性。我们在基于三个已建立的人类乳腺细胞系的模型上进行了研究，以考虑这种肿瘤的异质性（MCF10A、MCF7 和 MDA-MB-231 细胞）。我们的结果表明，DEK 的过表达与 DEK 与对应于基因启动子区域的组蛋白标记（H3K9ac、H3K4me3）之间的整体更高空间接近度相关，尽管它与 DEK 与基因增强子（H3K27ac）之间的空间接近度无关。此外，我们观察到非侵袭性细胞亚型的 DEK 和组蛋白标记的共定位分数低于高度侵袭性细胞系（MDA-MB-231）。因此，这项研究表明，DEK 在转录活性染色质区域的作用取决于乳腺癌细胞系的亚型。
