美国加州大学Quigley, David A小组及合作小组近日取得一项新成果。超深度RNA测序的综合分析揭示了在前列腺癌进展过程中，替代启动子的使用是激活致癌程序的一种机制。该研究于2024年6月13日发表于国际一流学术期刊《自然—细胞生物学》杂志上。

通过对274例良性前列腺组织、局部前列腺肿瘤和转移性去势抵抗性前列腺癌的活检组织进行深度RNA测序，研究人员发现，随着肿瘤的进展，替代启动子使用会增加，而替代启动子在肿瘤转录活性中起着不成比例的作用。雄激素受体(AR)是前列腺肿瘤活动的关键驱动因素，其表达与替代启动子使用升高相关。

小组发现AR、FOXA1和MYC是替代启动子激活的潜在驱动因素。DNA甲基化是肿瘤进展和谱系可塑性过程中替代启动子激活的可能机制。他们的数据表明，前列腺肿瘤激活替代启动子，放大肿瘤驱动因子(包括AR和MYC)的转录影响。

据悉，转录因子(TF)蛋白通过与调控区域结合来调节基因活性，最重要的是在基因启动子上。许多基因具有由不同转录因子结合的替代启动子(APs)。在肿瘤发育过程中，不同的转录因子活性在替代启动子中的作用尚不清楚。

附：英文原文

Title: Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression

Author: Zhang, Meng, Sjstrm, Martin, Cui, Xiekui, Foye, Adam, Farh, Kyle, Shrestha, Raunak, Lundberg, Arian, Dang, Ha X., Li, Haolong, Febbo, Phillip G., Aggarwal, Rahul, Alumkal, Joshi J., Small, Eric J., Maher, Christopher A., Feng, Felix Y., Quigley, David A.

Issue&Volume: 2024-06-13

Abstract: 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.

DOI: 10.1038/s41556-024-01438-3

Source: https://www.nature.com/articles/s41556-024-01438-3