Zhi Xiaofei, Tao Jinqiu, Zhang Lei, Tao Ran, Ma Lilin, Qin Jun
Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, China.
Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210029, China.
Cell Death Dis. 2016 Dec 29;7(12):e2569. doi: 10.1038/cddis.2016.435.
Epigenetic silencing of tumor suppressors contributes to the development and progression of colorectal cancer (CRC). We recently found that speckle-type POZ protein (SPOP) was significantly downregulated and the inactivation of SPOP promoted metastasis in CRC. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in CRC. Our results revealed that the core region of SPOP promoter was hypermethylated in CRC tissues and its methylation was correlated with poor survival. Transcription factor RXRA had a vital role in the regulation of SPOP gene. The data indicated that DNA methylation at -167 bp of the SPOP gene altered the binding affinity between transcription factor RXRA and SPOP promoter. Moreover, SPOP was found to associate with Gli2 and promoted its ubiquitination and degradation in CRC. Consequently, the expression level of Hh/Gli2 pathway-related apoptotic protein Bcl-2 was decreased and the function of resisting cell death was inhibited in CRC. It suggests that methylation status of SPOP promoter can be used as a novel epigenetic biomarker and a therapeutic target in CRC.
肿瘤抑制因子的表观遗传沉默促进了结直肠癌（CRC）的发生和发展。我们最近发现，斑点型POZ蛋白（SPOP）在结直肠癌中显著下调，SPOP的失活促进了结直肠癌的转移。本研究旨在阐明其在结直肠癌中的表观遗传改变、分子机制及临床意义。我们的结果显示，SPOP启动子的核心区域在结直肠癌组织中发生了高甲基化，其甲基化与较差的生存率相关。转录因子RXRA在SPOP基因的调控中起重要作用。数据表明，SPOP基因-167bp处的DNA甲基化改变了转录因子RXRA与SPOP启动子之间的结合亲和力。此外，在结直肠癌中发现SPOP与Gli2相互作用，并促进其泛素化和降解。因此，结直肠癌中Hh/Gli2通路相关凋亡蛋白Bcl-2的表达水平降低，抗细胞死亡功能受到抑制。这表明SPOP启动子的甲基化状态可作为结直肠癌一种新的表观遗传生物标志物和治疗靶点。
