超深度 RNA-seq 的综合分析揭示了在前列腺癌进展过程中，作为激活致癌程序的一种机制，存在着不同的启动子使用。
Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression.
机构信息
Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
出版信息
Nat Cell Biol. 2024 Jul;26(7):1176-1186. doi: 10.1038/s41556-024-01438-3. Epub 2024 Jun 13.
Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC.
转录因子 (TF) 蛋白通过与调控区域结合来调节基因活性，最重要的是与基因启动子结合。许多基因具有由不同 TF 结合的替代启动子 (AP)。在肿瘤发展过程中，AP 处的差异 TF 活性的作用知之甚少。在这里，我们使用深度 RNA 测序在 274 份良性前列腺组织、局部前列腺肿瘤和转移性去势抵抗性前列腺癌活检中进行了研究，结果表明，随着肿瘤的进展，AP 的使用增加，并且 AP 负责不成比例的肿瘤转录活性。雄激素受体 (AR) 的表达，即前列腺肿瘤活性的关键驱动因素，与 AP 使用的增加相关。我们确定 AR、FOXA1 和 MYC 是 AP 激活的潜在驱动因素。DNA 甲基化是肿瘤进展过程中 AP 激活和谱系可塑性的一种可能机制。我们的数据表明，前列腺肿瘤激活 AP 以放大肿瘤驱动因素（包括 AR 和 MYC）的转录影响。
Zotero 插件