SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer.
SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer.
复制标题
SOX30 是一种新型表观遗传沉默肿瘤抑制因子，通过转录激活肺癌中的 p53 促进肿瘤细胞凋亡。
作者：
Han F;Liu W;Jiang X;Shi X;Yin L;Ao L;Cui Z;Li Y;Huang C;Cao J;Liu J
尽管SOX家族成员在胚胎发育、细胞增殖和疾病中的重要作用已经得到了充分的研究，但SOX30在癌症中的功能作用和分子机制仍未得到很好的研究。在这里，我们首先通过全基因组甲基化筛选确定了SRY-box包含基因30(SOX30)是一个新的优先甲基化的基因。SOX30在100%(9/9)和70.83%(85/120)的肺癌组织中表达，而在正常肺组织(0/20)和癌旁肺组织中为8.0%(2/25)(P<0.01)。SOX30在SOX30未甲基化的正常肺组织和癌旁肺组织中表达，但在肺癌细胞系和SOX30高甲基化的原发肺癌组织中表达沉默或下调。去甲基化实验进一步证实SOX30的沉默受其高甲基化调控。SOX30的异位表达在体外诱导癌细胞凋亡，抑制细胞增殖，在体内抑制肿瘤形成，而SOX30的体外和体内表达下调则表现出相反的作用。在分子水平上，SOX30通过直接与P53启动子区域CACTTTG(+115~+121)结合，激活P53转录，从而发挥抗肿瘤作用，提示SOX30是一种新的P53转录激活因子。事实上，阻断P53可以减弱SOX30的肿瘤抑制作用。总体而言，这些发现表明SOX30是一种新的表观遗传学沉默的肿瘤抑制因子，通过直接调节P53的转录和表达发挥作用。这项研究为肺癌的发生机制提供了新的见解。
Although members of SOX family have been well documented for their essential roles in embryonic development, cell proliferation and disease, the functional role and molecular mechanism of SOX30 in cancer are largely unexplored. Here, we first identified SRY-box containing gene 30 (SOX30) as a novel preferentially methylated gene using genome-wide methylation screening. SOX30 hypermethylation was detected in 100% of lung cancer cell lines (9/9) and 70.83% (85/120) of primary lung tumor tissues compared with none (0/20) of normal and 8.0% (2/25) of peri-tumoral lung tissues (P<0.01). SOX30 was expressed in normal and peri-tumoral lung tissues in which SOX30 was unmethylated, but was silenced or downregulated in lung cancer cell lines and primary lung tumor tissues harboring a hypermethylated SOX30. De-methylation experiments further confirmed that silence of SOX30 was regulated by its hypermethylation. Ectopic expression of SOX30 induces cancer cell apoptosis with inhibiting proliferation in vitro and represses tumor formation in vivo, whereas knockdown of SOX30 demonstrates a reversed effect both in vitro and in vivo. At the molecular level, the antitumorigenic effect of SOX30 is mediated by directly binding to CACTTTG (+115 to +121) of p53 promoter region and activating p53 transcription, suggesting that SOX30 is a novel transcriptional activating factor of p53. Indeed, blockade of p53 attenuates the tumor inhibition of SOX30. Overall, these findings demonstrate that SOX30 is a novel epigenetic silenced tumor suppressor acting through direct regulation of p53 transcription and expression. This study provides novel insights on the mechanism of tumorigenesis in lung cancer.