An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer
An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer
复制标题
PRL-3 作为结直肠癌 H3K9 甲基化调节因子的表观遗传作用。
DOI：
10.1136/gutjnl-2011-301059
复制
发表时间：
2013-04-01
期刊：
影响因子：
24.5
通讯作者：
Li, Jianming
中科院分区：
文献类型：
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作者：
Liu, Yongxia;Zheng, Ping;Li, Jianming
目的研究结直肠癌（CRC）关键转移基因PRL-3在组蛋白去甲基化调控中的表观遗传学作用，以及巨onji结构域蛋白1B （JMJD1B）和JMJD2B在结直肠癌进展中的功能。方法对prl -3相关蛋白进行功能分布和类别富集分析。Western blotting和免疫荧光法检测核PRL-3。通过RNA干扰敲除JMJD1B、JMJD2B蛋白，确定PRL-3与JMJD1B、JMJD2B、PRL-3在组蛋白去甲基化中的作用。使用免疫组织化学分析方法对结直肠癌患者进行JMJD1B和JMJD2B的病例对照研究。进一步检测JMJD2B和JMJD1B的体外功能作用。结果prl -3相关蛋白中富集了组蛋白去甲基化酶JMJD1B和JMJD2B。在结直肠癌细胞及临床标本中均可见核PRL-3。核PRL-3在Dukes期晚期CRC患者中表达增加。PRL-3通过影响JMJD1B和JMJD2B的活性参与组蛋白甲基化的调控。JMJD1B蛋白的低表达与结直肠癌患者的淋巴结状态（p=0.032）、Dukes分级（p=0.008）和TNM分期（p=0.022）呈正相关。JMJD2B的高表达与结直肠癌患者的淋巴结状态（p=0.03）、Dukes分级（p=0.036）和肿瘤侵袭（p=0.003）呈正相关。功能缺失分析证实，JMJD2B促进了人结直肠癌细胞的增殖、集落形成和迁移。结论PRL-3作为组蛋白去甲基化的关键调控因子发挥了新的作用。JMJD1B似乎是一种候选的肿瘤抑制因子，JMJD2B似乎是CRC发生和进展中的潜在癌蛋白。
Objective This study investigated the epigenetic role of PRL-3, a key metastasis gene in colorectal cancer (CRC), as a regulator of histone demethylation and the functions of Jumonji domain-containing protein 1B (JMJD1B) and JMJD2B in the progression of CRC.Methods PRL-3-associated proteins were analysed using functional distribution and category enrichment analysis. Western blotting and immunofluorescence were used to detect nuclear PRL-3. The relationship between PRL-3 and JMJD1B or JMJD2B and the roles of JMJD1B, JMJD2B and PRL-3 in histone demethylation were determined after these proteins were knocked down using RNA interference. Case-control studies on JMJD1B and JMJD2B in patients with CRC were performed using immunohistochemical analysis. The in vitro functional effects of JMJD2B and JMJD1B were examined further.Results JMJD1B and JMJD2B, two histone demethylases, were enriched among PRL-3-associated proteins. Nuclear PRL-3 was observed in CRC cells and clinical samples of CRC. The expression of nuclear PRL-3 was increased in patients with CRC at more advanced Dukes' stages. PRL-3 was involved in the regulation of histone methylation by affecting the activities of JMJD1B and JMJD2B. A low expression of the JMJD1B protein was positively correlated with the lymph node status (p=0.032), Dukes' classification (p=0.008) and TNM staging (p=0.022) of patients with CRC. A high expression of JMJD2B was positively correlated with the lymph node status (p=0.03), Dukes' classification (p=0.036) and tumour invasion (p=0.003) of patients with CRC. A loss-of-function analysis confirmed that JMJD2B promoted the proliferation, colony formation and migration of human CRC cells.Conclusion Our data reveal a new role for PRL-3 as a key regulator of histone demethylation. JMJD1B seems to be a candidate tumour suppressor and JMJD2B seems to be a potential oncoprotein in the development and progression of CRC.