Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA.
J Natl Cancer Inst. 2024 Mar 7;116(3):421-433. doi: 10.1093/jnci/djad215.
Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression.
We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome.
This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling.
Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.
尽管跨膜丝氨酸蛋白酶 2 基因（TMPRSS2）与红细胞生成素转化特异性相关基因（ERG）融合，即 TMPRSS2-ERG，在前列腺癌中经常发生，但它对临床结果的影响仍存在争议。大约一半的 TMPRSS2-ERG 融合通过染色体间插入基因的缺失发生，其余通过插入性染色体重排发生。由于缺失衍生的 TMPRSS2-ERG 融合的前列腺癌比插入融合的前列腺癌更具侵袭性，因此我们研究了间质基因缺失对前列腺癌进展的影响。
我们对来自大量前列腺癌样本的转录组数据进行了无偏分析，并采用多种体外和体内模型结合遗传方法，对影响临床结果的最重要的间质基因缺失进行了特征描述。
该分析将 FAM3B 鉴定为排名最高的间质基因，其缺失与预后不良相关。FAM3B 缺失与不良临床结果的相关性扩展到融合阴性前列腺癌，其中 FAM3B 的下调是通过表观遗传印迹发生的。重要的是，FAM3B 缺失可驱动前列腺癌的进展。FAM3B 是雄激素受体自我调控反馈回路的中间介质。具体而言，雄激素受体通过结合内含子增强子来上调 FAM3B 表达，从而诱导增强子 RNA 并促进增强子-启动子环。反过来，FAM3B 减弱雄激素受体信号。
前列腺癌中 FAM3B 的缺失，无论是通过 TMPRSS2-ERG 易位还是表观遗传印迹，都会导致该自我调控环路的退出，从而释放雄激素受体活性并促进前列腺癌的进展。这些发现将 FAM3B 缺失确立为前列腺癌进展的新驱动因素，并支持 FAM3B 缺失作为生物标志物的实用性，以更好地定义侵袭性前列腺癌。
