Department of Urology, James Buchanan Brady Urological Institute, The Johns Hopkins University, School of Medicine, Baltimore, MD, 21287, USA.
Biomark Res. 2013 Jun 13;1(1):22. doi: 10.1186/2050-7771-1-22.
The Cancer Testis Antigens (CTAs) are a group of genes that are highly expressed in the normal testis and several types of cancer. Due to their restricted expression in normal adult tissues, CTAs have been attractive targets for immunotherapy and biomarker development. In this work, we discovered that Centrin 1 (CETN1) which is found in the centrosome of all eukaryotes, may be a member of this group and is highly expressed in prostate and pancreatic cancer. Three members of the centrin family of calcium binding proteins (CETN) are localized to the centrosome in all eukaryotes with CDC31 being the sole yeast homolog. CETN1 is a retrogene that probably arose from a retrotransposition of CETN2, an X-linked gene. A previous mouse study shows that CETN1 is expressed solely in the testis, while CETN2 is expressed in all organs.
In this work, we show that CETN1 is a new member of the growing group of CTAs. Through the mining of publicly available microarray data, we discovered that human CETN1 expression but not CETN2 or CETN3 is restricted to the testis. In fact, CETN1 is actually down-regulated in testicular malignancies compared to normal testis. Using q-PCR, CETN1 expression is shown to be highly up-regulated in cancer of the prostate and in pancreatic xenografts. Unexpectedly however, CETN1 expression was virtually absent in various cell lines until they were treated with the DNA demethylation agent 5'AZA-2'Deoxycytidine (AZA) but showed no increased expression upon incubation with Histone deacetylase inhibitor Trichostatin-A (TSA) alone. Additionally, like most CTAs, CETN1 appears to be an intrinsically disordered protein which implies that it may occupy a hub position in key protein interaction networks in cancer. Neither CETN1 nor CETN2 could compensate for loss of CDC31 expression in yeast which is analogous to published data for CETN3.
This work suggests that CETN1 is a novel CTA with expression in cancer of the prostate and pancreas. In cell lines, the expression is probably regulated by promoter methylation, while the method of regulation in normal adult tissues remains unknown.
癌症睾丸抗原（CTAs）是一组在正常睾丸和几种类型的癌症中高度表达的基因。由于其在正常成人组织中的表达受限，CTAs 一直是免疫治疗和生物标志物开发的有吸引力的目标。在这项工作中，我们发现 Centrin 1（CETN1），存在于所有真核生物的中心体中，可能是该基因家族的一员，在前列腺癌和胰腺癌中高度表达。三种钙结合蛋白的 Centrin 家族成员（CETN）定位于所有真核生物的中心体，而 CDC31 是唯一的酵母同源物。CETN1 是一个反转录基因，可能是从 X 连锁基因 CETN2 的反转录转位产生的。以前的小鼠研究表明，CETN1 仅在睾丸中表达，而 CETN2 则在所有器官中表达。
在这项工作中，我们表明 CETN1 是不断增长的 CTAs 基因家族的新成员。通过挖掘公开的微阵列数据，我们发现人类 CETN1 的表达（而非 CETN2 或 CETN3）仅限于睾丸。事实上，与正常睾丸相比，CETN1 在睾丸恶性肿瘤中实际上是下调的。使用 q-PCR，发现 CETN1 在前列腺癌和胰腺异种移植瘤中高度上调。然而出乎意料的是，CETN1 的表达在各种细胞系中几乎不存在，直到用 DNA 去甲基化剂 5'AZA-2'Deoxycytidine（AZA）处理后才出现高度上调，但单独用组蛋白去乙酰化酶抑制剂 Trichostatin-A（TSA）孵育后没有增加表达。此外，与大多数 CTAs 一样，CETN1 似乎是一种内在无序的蛋白质，这意味着它可能在癌症中的关键蛋白质相互作用网络中占据枢纽位置。酵母中既没有 CETN1 也没有 CETN2 可以弥补 CDC31 表达的缺失，这与发表的关于 CETN3 的数据类似。
这项工作表明 CETN1 是一种新的 CTA，在前列腺癌和胰腺癌中表达。在细胞系中，表达可能受启动子甲基化的调节，而在正常成人组织中的调节方式尚不清楚。
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