Chen Haiqi, Jiang Yu, Mruk Dolores D, Cheng C Yan
The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, New York, NY, USA.
College of Pharmacy, University of Iowa, Iowa City, IA, USA.
Adv Exp Med Biol. 2021;1288:69-93. doi: 10.1007/978-3-030-77779-1_4.
Cancer/testis (CT) antigens are proteins aberrantly overexpressed in various tumorigenic cells, but they can also be normally expressed in the mammalian germline. Most CT antigens are highly immunogenic and known to be involved in cancer cell proliferation and tumor metastasis. A recent genome-wide analysis systematically identified CT antigen expression in 19 cancer types, significantly expanding the repertoire of CT antigens by 5-fold, from over 200 to approximately 1000. However, their function and regulation in tumorigenesis remain poorly understood. The shared functional characteristics between germ cells and cancer cells, if methodically defined, offer a unique gateway to understanding the regulation of CT antigens in cancers by studying gametogenesis. Nonetheless, such studies also provide insightful information on the role of CT antigens in spermatogenesis. Herein, we analyzed publicly available next generation sequencing datasets generated from normal adult testes in rodents, primordial germ cells and cancer samples across a series of published studies and databases. Based on these analyses, we report that a subset of CT antigens belonged to the core fitness gene family. Furthermore, super-enhancers both in normal testes and various cancers controlled specific CT antigens. We found that DNA methylation of CT antigens, such as TEX101 and TAF7L, was inversely correlated with their expression in both normal primordial germ cells and various cancers, which was mediated at least partly by DNA methyltransferase1 (DNMT1). By analyzing data from a testis knockout model, we showed that TAF7L could further influence the expression of additional CT antigens, which also held true in tumors. These findings not only confirmed the previous notion that CT antigens regulate cancer dynamics, but also showed that understanding the regulation of CT antigens during gametogenesis can offer new insights for cancer research.
癌胚抗原（CT）是在各种致瘤细胞中异常高表达的蛋白质，但它们也可在哺乳动物生殖系中正常表达。大多数CT抗原具有高度免疫原性，并且已知参与癌细胞增殖和肿瘤转移。最近的一项全基因组分析系统地鉴定了19种癌症类型中的CT抗原表达，使CT抗原的种类显著增加了5倍，从200多种增加到约1000种。然而，它们在肿瘤发生中的功能和调控仍知之甚少。如果能系统地定义生殖细胞和癌细胞之间的共同功能特征，那么通过研究配子发生，就为理解癌症中CT抗原的调控提供了一个独特的途径。尽管如此，这类研究也为CT抗原在精子发生中的作用提供了有深刻见解的信息。在此，我们分析了一系列已发表的研究和数据库中来自啮齿动物正常成年睾丸、原始生殖细胞和癌症样本的公开可用的下一代测序数据集。基于这些分析，我们报告说，一部分CT抗原属于核心适应性基因家族。此外，正常睾丸和各种癌症中的超级增强子控制着特定的CT抗原。我们发现，CT抗原如TEX101和TAF7L的DNA甲基化与其在正常原始生殖细胞和各种癌症中的表达呈负相关，这至少部分是由DNA甲基转移酶1（DNMT1）介导的。通过分析睾丸敲除模型的数据，我们表明TAF7L可以进一步影响其他CT抗原的表达，这在肿瘤中也是如此。这些发现不仅证实了之前关于CT抗原调节癌症动态的观点，而且还表明，了解配子发生过程中CT抗原的调控可为癌症研究提供新的见解。
