Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People’s Republic of China.
Gut. 2013 Apr;62(4):571-81. doi: 10.1136/gutjnl-2011-301059. Epub 2012 Feb 16.
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.
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.
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.
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.
本研究探讨了 PRL-3 的表观遗传作用，PRL-3 是结直肠癌（CRC）中的一个关键转移基因，作为组蛋白去甲基化的调节剂，以及 Jumonji 结构域包含蛋白 1B（JMJD1B）和 JMJD2B 在 CRC 进展中的功能。
采用功能分布和类别富集分析分析 PRL-3 相关蛋白。采用 Western blot 和免疫荧光检测核 PRL-3。用 RNA 干扰敲低这些蛋白后，确定 PRL-3 与 JMJD1B 或 JMJD2B 的关系以及 JMJD1B、JMJD2B 和 PRL-3 在组蛋白去甲基化中的作用。采用免疫组织化学分析对 CRC 患者的 JMJD1B 和 JMJD2B 进行病例对照研究。进一步检测 JMJD2B 和 JMJD1B 的体外功能效应。
JMJD1B 和 JMJD2B 两种组蛋白去甲基酶在 PRL-3 相关蛋白中富集。在 CRC 细胞和 CRC 临床样本中观察到核 PRL-3。在 Dukes 分期较高的 CRC 患者中，核 PRL-3 的表达增加。PRL-3 通过影响 JMJD1B 和 JMJD2B 的活性参与组蛋白甲基化的调节。JMJD1B 蛋白表达降低与患者的淋巴结状态（p=0.032）、Dukes 分类（p=0.008）和 TNM 分期（p=0.022）呈正相关。JMJD2B 高表达与患者的淋巴结状态（p=0.03）、Dukes 分类（p=0.036）和肿瘤侵袭（p=0.003）呈正相关。功能丧失分析证实，JMJD2B 促进人 CRC 细胞的增殖、集落形成和迁移。
我们的数据揭示了 PRL-3 作为组蛋白去甲基化关键调节剂的新作用。JMJD1B 似乎是一种候选抑癌基因，JMJD2B 似乎是 CRC 发生和发展的潜在癌基因。
