Zhang Lian, Zhang Qian, Li LiLi, Wang Zhaohui, Ying Jianming, Fan Yu, He Qun, Lv Tianjing, Han Wenke, Li Jun, Yang Yang, Xu Ben, Wang Lu, Liu Qianling, Sun Yinghao, Guo Yinglu, Tao Qian, Jin Jie
Department of Urology, National Research Center for Genitourinary Oncology, Peking University First Hospital and Institute of Urology, Beijing, China.
J Mol Med (Berl). 2015 Jun;93(6):691-701. doi: 10.1007/s00109-015-1255-5. Epub 2015 Feb 5.
Deleted in lung and esophageal cancer 1 (DLEC1), located at 3p22-p21.3, is involved in the carcinogenesis of multiple cancers, but its role in prostate cancer (PrCa) remains unclear. Here, we studied the epigenetic alteration of DLEC1 and its functions in prostate cancer. We found that DLEC1 was highly expressed in normal prostate tissues, normal prostatic epithelium cell line (RWPE-1), and benign prostatic hyperplasia cell line (BPH-1), but frequently downregulated by promoter methylation in PrCa cell lines. Pharmacologic demethylation could restore DLEC1 expression. DLEC1 was downregulated in prostate tumor tissues compared with their adjacent non-malignant tissues. DLEC1 was methylated in 76/110 primary tumors, but rarely in benign prostatic hyperplasia tissues. DLEC1 methylation was associated with higher PSA levels (p = 0.016), higher Gleason scores (p = 0.015), and more advanced tumor stages (p = 0.003). Furthermore, DLEC1 methylation was detected in 11/30 urine sediment samples from PrCa patients, but seldom in ones from BPH patients. Ectopic expression of DLEC1 inhibited the colony formation of PrCa cells, through inducing cell apoptosis. DLEC1 also suppressed PrCa cell migration. Moreover, DLEC1 inhibited NF-κB transcription activity in PrCa and HEK293 cells. Taken together, our data demonstrate that DLEC1 functions as a tumor suppressor but is frequently methylated in prostate cancer. DLEC1 methylation is associated with prostate cancer progression, which could be a non-invasive epigenetic biomarker for PrCa diagnosis.
• Promoter methylation of DLEC1 is a potential prognostic biomarker for PrCa. • DLEC1, a functional tumor suppressor, is frequently methylated in PrCa. • DLEC1 suppresses prostate cancer growth and metastatic behavior. • DLEC1 mediates tumor-suppressive activities through NF-κB signaling.
肺癌和食管癌缺失基因1（DLEC1）位于3p22 - p21.3，参与多种癌症的致癌过程，但其在前列腺癌（PrCa）中的作用仍不清楚。在此，我们研究了DLEC1的表观遗传改变及其在前列腺癌中的功能。我们发现DLEC1在正常前列腺组织、正常前列腺上皮细胞系（RWPE - 1）和良性前列腺增生细胞系（BPH - 1）中高表达，但在前列腺癌细胞系中常因启动子甲基化而下调。药物去甲基化可恢复DLEC1表达。与相邻的非恶性组织相比，DLEC1在前列腺肿瘤组织中表达下调。在110例原发性肿瘤中有76例DLEC1发生甲基化，而在良性前列腺增生组织中很少见。DLEC1甲基化与较高的前列腺特异抗原（PSA）水平（p = 0.·016）、较高的Gleason评分（p = 0.015）以及更晚期的肿瘤分期（p = 0.003）相关。此外，在30例前列腺癌患者的尿液沉淀物样本中有11例检测到DLEC1甲基化，而在良性前列腺增生患者的样本中很少见。DLEC1的异位表达通过诱导细胞凋亡抑制前列腺癌细胞的集落形成。DLEC1还抑制前列腺癌细胞迁移。此外，DLEC1抑制前列腺癌和人胚肾293（HEK293）细胞中的核因子κB（NF - κB）转录活性。综上所述，我们的数据表明DLEC1作为一种肿瘤抑制因子，但在前列腺癌中常发生甲基化。DLEC1甲基化与前列腺癌进展相关，这可能是一种用于前列腺癌诊断的非侵入性表观遗传生物标志物。
• DLEC1启动子甲基化是前列腺癌的一种潜在预后生物标志物。
• DLEC1是一种功能性肿瘤抑制因子，在前列腺癌中常发生甲基化。
• DLEC1抑制前列腺癌的生长和转移行为。
• DLEC1通过NF - κB信号传导介导肿瘤抑制活性。
