PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer
PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer
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DOI：
10.1038/onc.2014.219
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发表时间：
2015-05-28
期刊：
影响因子：
8
通讯作者：
Chun, Y-S
中科院分区：
文献类型：
--
作者：
Lee, K-H;Park, J-W;Chun, Y-S
植物同源结构域指2（PHF 2）通过使H3 K9-Me 2去甲基化而在基因表达的表观遗传调控中起作用。几项全基因组研究表明，包括PHF 2基因在内的染色体区域在包括结直肠癌在内的一些癌症中经常缺失，这一发现鼓励我们研究PHF 2的肿瘤抑制作用。由于p53在结肠癌中是一个关键的肿瘤抑制因子，我们测试了PHF 2是p53的表观遗传调节因子的可能性。PHF 2与p53相关，从而促进基因毒性应激下癌细胞中p53驱动的基因表达。PHF 2通过使抑制性H3 K9-Me 2标记去甲基化来转化有利于转录的染色质。在HCT 116异种移植模型中，发现PHF 2是奥沙利铂和多柔比星的抗癌作用所必需的。在PHF 2缺陷的异种移植物中，两种药物都能诱导p53的表达，但其下游产物p21却不能，这表明在没有PHF 2的情况下p53不能被激活。为了寻找PHF 2作用的临床证据，我们分析了PHF 2、p53和p21在人结肠癌组织和患者的癌旁正常组织中的表达。PHF 2在癌组织中下调，并且在表达功能性p53的癌症中PHF 2与p21相关。结肠癌和胃癌组织芯片显示PHF 2和p21的表达呈正相关。使用Oncomine数据库的信息学分析也支持我们的观点，即PHF 2在结肠癌和胃癌中下调。基于这些发现，我们提出PHF 2在癌症发展中与p53相关，并在化疗中确保p53介导的细胞死亡。
Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy.