Mina可能作为组蛋白赖氨酸脱甲基酶修饰H3K4/H3K9甲基化并抑制肝癌侵袭

Epigenetics has been extensively studied in cancer research.By post-transcriptional modification of histones, expression of oncogenes or anti-oncogenes can be changed.Many "epigenetic drugs" has been proved to be used in clinical cancer therapy.Preliminary studies suggested that Mina (Myc Induced Nuclear Antigen) functioned as downstream target of c-myc associated with cell proliferation. However, its real identity remained still unknown.Presumed from chemical structure,128-271 amino acids of Mina contains Jmjc domain which is characteristic of histone demethylases Jmjc family involved in histone methylation and chromatin reconstruction. We found that overexpression of Mina in hepatocellular carcinoma significantly inhibited proliferation, migration and invasion of cancer cells in vitro and was associated with improved prognosis.Further studies linked Mina up-regulation to histone H3K4/H3K9 demethylation, indicating that Mina probably functioned as histone demethylase. These evidences not only help to uncover the real identity of Mina independent of c-myc, but also provide potential target for epigenetic therapy of liver cancer. However, thorough experiments are needed to elucidate molecular mechanisms of cross-talk between Mina and histone methylation in HCC.

表观遗传学是肿瘤研究的热点，通过组蛋白甲基化等转录后修饰可引起癌基因或抑癌基因表达的改变，"表观药物"在肿瘤治疗中的应用也初显成效。最初的研究发现Mina（Myc Induce Nuclear Antigen）是c-myc的下游靶基因、参与细胞增殖过程，然而这无法揭示它独立的生物学身份。从结构上推测，Mina基因第128-271位氨基酸含有一个Jmjc结构域，后者是组蛋白脱甲基酶Jmjc家族的特征，参与组蛋白甲基化和染色体重塑。我们前期的研究发现，肝癌Mina高表达可抑制细胞增殖、迁移和侵袭并改善患者预后。进一步的研究发现肝癌Mina表达与组蛋白H3K4/H3K9甲基化水平显著负相关，提示它可能是潜在的组蛋白脱甲基化酶。这不仅有助于揭示它独立于c-myc之外的真实身份，也为肝癌的表观遗传学治疗提供潜在的靶点。然而，Mina与组蛋白甲基化"交叉对话"涉及的分子机制需要更深入的研究予以阐释。

表观遗传学是肿瘤研究的热点，通过组蛋白甲基化等转录后修饰可引起癌基因或抑癌基因表达的改变。Mina（Myc Induce Nuclear Antigen）最初被证实为c-myc的下游靶基因、参与细胞增殖过程。从结构上推测，Mina基因第128-271位氨基酸含有一个Jmjc结构域，后者是组蛋白脱甲基酶Jmjc家族的特征，参与组蛋白甲基化和染色体重塑。因此，我们推测MINA可能与组蛋白甲基化调控有关。.通过该课题我们证实，Mina高表达可抑制肝癌细胞系HepG2/SMMC7721增殖、迁移和侵袭。肝癌组织Mina蛋白低表达与细胞分化差、癌栓阳性和高TNM分期显著相关。癌组织Mina蛋白低表达是肝癌患者术后复发和死亡风险增高的独立危险因素。此外，肝癌Mina表达与组蛋白H3K4/H3K9甲基化水平显著负相关。.综上，MINA可能作为组蛋白甲基化调控酶抑制肝癌的侵袭转移。这首次揭示了MINA独立于c-myc之外的真实身份，也为肝癌的表观遗传学调控提供潜在的靶点，具有重要的临床应用价值。.此外，我们尚研究了GATA家族转录因子（GATA2,GATA4,GATA5,GATA6）在肝癌的表达与预后的关系。结果显示：肝癌组织GATA2低表达是患者不良预后的独立危险因素，下调肝癌细胞系HepG2细胞GATA2表达可促进细胞增殖、迁移和侵袭。提示GATA2可能作为肝癌治疗的潜在靶点，具有一定的临床价值。