Department of Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 50007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR- Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, Uttar Pradesh, 201 002, India.
Department of Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 50007, India.
Free Radic Biol Med. 2021 Nov 20;176:62-72. doi: 10.1016/j.freeradbiomed.2021.09.010. Epub 2021 Sep 14.
The cancer-testis antigen CTCFL/BORIS (Brother of Regulator of Imprinted Sites) also known, as a paralog of CTCF -the "master weaver of the genome" is a key transcriptional regulator. Both CTCF and BORIS can bind to the same promoter sequence and recruit diverse proteins. BORIS is also known to be associated with actively translating ribosomes suggesting new roles of BORIS in gene expression. Various studies have attempted to elucidate the role of BORIS in different cell types for the development of targeted therapy depending on molecular signatures and genetic aberrations associated with the disease type. The current study is focused on its role in neuroblastoma. Here, we have deciphered the role of BORIS on TGFβ1 pathway which is highly affected by embryonic CTCFL expression. BORIS stabilized the SMAD3 and SMAD4 transcripts leading to prolonged TGFβ activation. Further, loss of BORIS abrogated both the canonical and non-canonical TGFβ signaling suggesting the dependency of TGFβ on BORIS. The effect on the metabolic profile of the neuroblastoma cells were analyzed with change in BORIS expression levels. Also, ectopic expression of BORIS leads to Drp1 phosphorylation (Ser616) enhancing mitochondrial fission followed by a switch in cellular metabolism towards glycolysis. This cellular metabolism switch was in turn supported with a reduction in oxygen consumption rate upon BORIS expression. Interestingly methylome analysis revealed patterns of global histone methylation, a mechanism that regulate important signaling pathways in neuroblastoma. This study analyzes the consequence of BORIS expression in neuroblastoma cells and thereby elucidate its downstream targets, which could help in designing effective therapeutic for treating neuroblastoma. Similar results were obtained in both MYCN amplified and non-MYCN neuroblastoma cell lines, indicating a common mechanism of BORIS/CTCFL action in neuroblastoma.
癌症-睾丸抗原 CTCFL/BORIS（印迹位点调节因子的兄弟）也被称为 CTCF 的同源物-“基因组的主要编织者”，是一种关键的转录调节剂。CTCF 和 BORIS 均可结合到相同的启动子序列并募集多种蛋白。BORIS 也与正在翻译的核糖体有关，这表明 BORIS 在基因表达中具有新的作用。各种研究试图阐明 BORIS 在不同细胞类型中的作用，以针对与疾病类型相关的分子特征和遗传异常开发靶向治疗。本研究集中在其在神经母细胞瘤中的作用。在这里，我们已经阐明了 BORIS 在 TGFβ1 途径中的作用，该途径受胚胎 CTCFL 表达的高度影响。BORIS 稳定了 SMAD3 和 SMAD4 转录本，导致 TGFβ 激活延长。此外，BORIS 的缺失消除了经典和非经典 TGFβ 信号转导，表明 TGFβ 依赖于 BORIS。通过改变 BORIS 表达水平分析了神经母细胞瘤细胞的代谢特征。此外，BORIS 的异位表达导致 Drp1 磷酸化（Ser616），增强线粒体裂变，随后细胞代谢向糖酵解转变。这种细胞代谢转变得到了 BORIS 表达时耗氧量降低的支持。有趣的是，甲基组分析揭示了组蛋白整体甲基化的模式，这是调节神经母细胞瘤中重要信号通路的一种机制。本研究分析了 BORIS 在神经母细胞瘤细胞中的表达后果，从而阐明了其下游靶标，这有助于设计治疗神经母细胞瘤的有效疗法。在 MYCN 扩增和非 MYCN 神经母细胞瘤细胞系中均获得了相似的结果，表明 BORIS/CTCFL 在神经母细胞瘤中的作用存在共同机制。
