Division of Biosciences, Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK.
Division of Biosciences, Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London, UK.
Sci Rep. 2024 Jan 2;14(1):198. doi: 10.1038/s41598-023-50640-0.
The proteostasis network (PN) is a collection of protein folding and degradation pathways that spans cellular compartments and acts to preserve the integrity of the proteome. The differential expression of PN genes is a hallmark of many cancers, and the inhibition of protein quality control factors is an effective way to slow cancer cell growth. However, little is known about how the expression of PN genes differs between patients and how this impacts survival outcomes. To address this, we applied unbiased hierarchical clustering to gene expression data obtained from primary and metastatic cutaneous melanoma (CM) samples and found that two distinct groups of individuals emerge across each sample type. These patient groups are distinguished by the differential expression of genes encoding ATP-dependent and ATP-independent chaperones, and proteasomal subunits. Differences in PN gene expression were associated with increased levels of the transcription factors, MEF2A, SP4, ZFX, CREB1 and ATF2, as well as markedly different survival outcomes. However, surprisingly, similar PN alterations in primary and metastatic samples were associated with discordant survival outcomes in patients. Our findings reveal that the expression of PN genes demarcates CM patients and highlights several new proteostasis sub-networks that could be targeted for more effective suppression of CM within specific individuals.
蛋白质稳态网络 (PN) 是一组跨越细胞区室的蛋白质折叠和降解途径,其作用是维持蛋白质组的完整性。PN 基因的差异表达是许多癌症的标志,而抑制蛋白质质量控制因子是减缓癌细胞生长的有效方法。然而,人们对患者之间 PN 基因表达的差异以及这如何影响生存结果知之甚少。为了解决这个问题,我们应用无偏分层聚类方法对原发性和转移性皮肤黑色素瘤 (CM) 样本中的基因表达数据进行了分析,结果发现两种不同类型的个体出现在每个样本类型中。这些患者群体的区别在于编码 ATP 依赖和 ATP 非依赖伴侣和蛋白酶体亚基的基因的差异表达。PN 基因表达的差异与转录因子 MEF2A、SP4、ZFX、CREB1 和 ATF2 的水平升高有关,同时也与明显不同的生存结果有关。然而,令人惊讶的是,原发性和转移性样本中的类似 PN 改变与患者的生存结果不一致。我们的研究结果表明,PN 基因的表达可以区分 CM 患者,并突出了几个新的蛋白质稳态子网络,这些子网络可能成为针对特定个体中 CM 进行更有效抑制的目标。