Kido Tatsuo, Li Yunmin, Tanaka Yuichiro, Dahiya Rajvir, Chris Lau Yun-Fai
Division of Cell and Developmental Genetics, Department of Medicine, Veterans Affairs Medical Center, San Francisco, California, USA.
Institute for Human Genetics, University of California, San Francisco, California, USA.
Oncotarget. 2019 Feb 19;10(15):1491-1506. doi: 10.18632/oncotarget.26673.
TSPX is a tumor suppressor gene located at Xp11.22, a prostate cancer susceptibility locus. It is ubiquitously expressed in most tissues but frequently downregulated in various cancers, including lung, brain, liver and prostate cancers. The C-terminal acidic domain (CAD) of TSPX is crucial for the tumor suppressor functions, such as inhibition of cyclin B/CDK1 phosphorylation and androgen receptor transactivation. Currently, the exact role of the TSPX CAD in transcriptional regulation of downstream genes is still uncertain. Using different variants of TSPX, we showed that overexpression of either TSPX, that harbors a CAD, or a CAD-truncated variant (TSPX[∆C]) drastically retarded cell proliferation in a prostate cancer cell line LNCaP, but cell death was induced only by overexpression of TSPX. Transcriptome analyses showed that TSPX or TSPX[∆C] overexpression downregulated multiple cancer-drivers/oncogenes, including MYC and MYB, in a CAD-dependent manner and upregulated various tumor suppressors in a CAD-independent manner. Datamining of transcriptomes of prostate cancer specimens in the Cancer Genome Atlas (TCGA) dataset confirmed the negative correlation between the expression level of TSPX and those of MYC and MYB in clinical prostate cancer, thereby supporting the hypothesis that the CAD of TSPX plays an important role in suppression of cancer-drivers/oncogenes in prostatic oncogenesis.
TSPX是一种肿瘤抑制基因，位于Xp11.22，即前列腺癌易感位点。它在大多数组织中普遍表达，但在包括肺癌、脑癌、肝癌和前列腺癌在内的各种癌症中经常下调。TSPX的C端酸性结构域（CAD）对肿瘤抑制功能至关重要，如抑制细胞周期蛋白B/细胞周期蛋白依赖性激酶1磷酸化和雄激素受体反式激活。目前，TSPX CAD在下游基因转录调控中的确切作用仍不确定。我们使用不同的TSPX变体表明，含有CAD的TSPX或CAD截短变体（TSPX[∆C]）的过表达在前列腺癌细胞系LNCaP中显著抑制细胞增殖，但仅TSPX过表达诱导细胞死亡。转录组分析表明，TSPX或TSPX[∆C]过表达以CAD依赖的方式下调多个癌症驱动基因/癌基因，包括MYC和MYB，并以CAD非依赖的方式上调各种肿瘤抑制因子。对癌症基因组图谱（TCGA）数据集中前列腺癌标本转录组的挖掘证实了临床前列腺癌中TSPX表达水平与MYC和MYB表达水平之间的负相关，从而支持了TSPX的CAD在前列腺癌发生过程中抑制癌症驱动基因/癌基因方面起重要作用的假设。
