Fibroblast activation protein (FAP)是一种膜结合性血清酶，既可以作为二肽基肽酶，也可以作为胶原酶。近年来，由于FAP在多种肿瘤细胞群体，包括各种癌症类型的癌细胞中的特定上调，因此引起了相当大的关注，使FAP成为潜在的治疗靶点。然而，相对较少的论文关注促使特定细胞表达FAP基因的机制。我们发现，在具有不同FAP表达水平的几个细胞系中，两个FAP启动子变体（短和长）的活性与内源性FAP mRNA表达水平之间没有相关性。这表明其他机制可能负责FAP基因的特定转录调控。我们分析了FAP阳性和FAP阴性细胞系中已知表观遗传和结构染色质标记的分布，并确定了FAP基因座位中的两个潜在增强子样元件（E1和E2）。我们证实了H3K27ac在FAP表达细胞中的潜在增强子区域中的特异性富集。在功能测试中，两个元素都独立于彼此具有增强子活性，使FAP启动子变异体的活性在FAP表达细胞系中比在FAP阴性细胞系中更大地增加。转录因子AP-1，CEBPB和STAT3可能参与肿瘤中的FAP激活。我们假设存在FAP和STAT3之间的正反馈环路，这可能对开发新的癌症治疗方法具有影响。版权所有 © 2023 Antonova、Gnatenko、Kotova、Pleshkan、Kuzmich、Didych、Sverdlov和Alekseenko。

Fibroblast activation protein (FAP) is an integral membrane serine protease that acts as both dipeptidyl peptidase and collagenase. In recent years, FAP has attracted considerable attention due to its specific upregulation in multiple types of tumor cell populations, including cancer cells in various cancer types, making FAP a potential target for therapy. However, relatively few papers pay attention to the mechanisms driving the cell-specific expression of the FAP gene. We found no correlation between the activities of the two FAP promoter variants (short and long) and the endogenous FAP mRNA expression level in several cell lines with different FAP expression levels. This suggested that other mechanisms may be responsible for specific transcriptional regulation of the FAP gene. We analyzed the distribution of known epigenetic and structural chromatin marks in FAP-positive and FAP-negative cell lines and identified two potential enhancer-like elements (E1 and E2) in the FAP gene locus. We confirmed the specific enrichment of H3K27ac in the putative enhancer regions in FAP-expressing cells. Both the elements exhibited enhancer activity independently of each other in the functional test by increasing the activity of the FAP promoter variants to a greater extent in FAP-expressing cell lines than in FAP-negative cell lines. The transcription factors AP-1, CEBPB, and STAT3 may be involved in FAP activation in the tumors. We hypothesized the existence of a positive feedback loop between FAP and STAT3, which may have implications for developing new approaches in cancer therapy.Copyright © 2023 Antonova, Gnatenko, Kotova, Pleshkan, Kuzmich, Didych, Sverdlov and Alekseenko.