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Abstract：
Background/Objectives: Preferentially expressed antigen in melanoma (PRAME), a member of the cancer testis antigen family, is a promising target for cancer immunotherapy. Understanding the epigenetic mechanisms involved in the regulation of PRAME expression might be crucial for optimizing anti-PRAME treatments. Methods: Three malignancies of different lineages (sinonasal melanoma, testicular seminoma, and synovial sarcoma), in which immunohistochemical (IHC) reactivity for PRAME is a common yet variable feature, were studied. The expression of PRAME, ten-eleven translocation demethylase 1 (TET1), and DNA methyltransferase (DNMT) 3A and 3B were evaluated using immunohistochemistry. Moreover, the expression of two epigenetic marks, 5-hydroxymethylcytosine (5hmC) and histone 3 acetylation (H3ac), was tested. Results: All PRAME-positive tumors expressed medium-to-high levels of H3ac but differed considerably with respect to other markers. In seminomas, PRAME expression correlated with TET1, but in melanomas and synovial sarcomas, it correlated with both DNMTs and DNMT3A, respectively. Conclusions: PRAME expression was not determined by a balance between the global expression of DNA methylating/demethylating enzymes. However, histone acetylation may be one of the epigenetic mechanisms involved in PRAME regulation. Thus, the therapeutic combination of histone deacetylase inhibitors and PRAME immunotherapy merits further investigation.
摘要：
背景/目标：黑色素瘤中优先表达的抗原（PRAME），癌症睾丸抗原家族的成员，是癌症免疫疗法的一个有希望的靶点。了解PRAME表达调控中涉及的表观遗传机制可能对于优化抗PRAME治疗至关重要。方法：三种不同谱系的恶性肿瘤（鼻窦黑色素瘤，睾丸精原细胞瘤，和滑膜肉瘤），其中PRAME的免疫组织化学（IHC）反应性是一个常见但可变的特征，被研究过。PRAME的表达，十一点转运去甲基酶1（TET1），使用免疫组织化学评估DNA甲基转移酶（DNMT）3A和3B。此外，两个表观遗传标记的表达，5-羟甲基胞嘧啶（5hmC）和组蛋白3乙酰化（H3ac），经过测试。结果：所有PRAME阳性肿瘤均表达中等至高水平的H3ac，但与其他标记物相比差异很大。在精原细胞瘤中，PRAME表达与TET1相关，但在黑色素瘤和滑膜肉瘤中，它与DNMT和DNMT3A相关，分别。结论：PRAME表达不是通过DNA甲基化/去甲基化酶的整体表达之间的平衡来确定的。然而,组蛋白乙酰化可能是参与PRAME调控的表观遗传机制之一。因此，组蛋白去乙酰化酶抑制剂和PRAME免疫治疗的治疗组合值得进一步研究.
