前列腺特异性膜抗原（PSMA）是前列腺癌重要的细胞表面靶标。关于去势抵抗性前列腺癌（mCRPC）中PSMA组织表达异质性的数据有限。此外，调控PSMA表达的机制（由FOLH1基因编码）也不是很清楚。在这里，我们证明了PSMA在不同转移位点和mCRPC分子亚型之间存在异质性表达。在一个快速尸检队列中，每个患者采样了多个转移位点，我们发现13/52（25％）的病例没有检测到PSMA，23/52（44％）显示了个体转移之间PSMA表达的异质性，其中33（63％）个病例至少有一个PSMA阴性位点。PSMA阴性肿瘤显示出不同的转录谱，包括可治疗的靶标MUC1的表达。PSMA的丧失与FOLH1位点上的表观遗传学变化（包括CpG甲基化的增加和组蛋白3赖氨酸27（H3K27）乙酰化的丧失）有关。组蛋白去乙酰化酶（HDAC）抑制剂的治疗逆转了这种表观遗传抑制，并在体内和体外恢复了PSMA的表达。总之，这些数据提供了关于mCRPC中PSMA表达模式和调节的新见解，并暗示表观遗传学疗法，特别是HDAC抑制剂，可用于增加PSMA水平。

Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13/52 (25%) cases had no detectable PSMA and 23/52 (44%) showed heterogeneous PSMA expression across individual metastases with 33 (63%) cases harboring at least one PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles, including the expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide novel insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies, in particular HDAC inhibitors, can be used to augment PSMA levels.