Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mod Pathol. 2011 Sep;24(9):1272-80. doi: 10.1038/modpathol.2011.76. Epub 2011 May 13.
Glycine N-methyltransferase (GNMT) has a role in the metabolism of methionine as well as in gluconeogenesis. It has recently been reported that the GNMT gene acts as a tumor-susceptible gene. However, little is known about the specific function of GNMT in carcinogenesis and malignant progression. To better our understanding of the function of GNMT in prostate cancer, we used siRNAs to examine the effects of GNMT knockdown on cell proliferation and the cell cycle. In addition, the relation between immunohistochemical GNMT expression and clinicopathologic parameters was investigated in 148 prostate cancer tissues. Here, we show that siRNA-mediated GNMT knockdown results in an inhibition of proliferation, and induces G1 arrest and apoptosis in prostate cancer cell lines. Moreover, high cytoplasmic GNMT expression was also correlated with a higher Gleason score (P<0.001) and higher pT stage (P=0.027). The patients with high GNMT cytoplasmic expression showed significantly lower disease-free survival rates than patients with low expression (P<0.001). High GNMT cytoplasmic expression had a significant impact on patient disease-free survival in multivariate analysis (P=0.005). This is the first investigation to reveal the novel finding that GNMT may have an important role in promoting prostate cancer cell growth via the regulation of apoptosis and contribute to the progression of prostate cancer. The modulation of GNMT expression or function may be a strategy for developing novel therapeutics for prostate cancer. GNMT may represent a novel marker of malignant progression and poor prognosis in prostate cancer.
甘氨酸 N-甲基转移酶（GNMT）在蛋氨酸代谢以及糖异生中具有作用。最近有报道称，GNMT 基因作为肿瘤易感性基因发挥作用。然而，关于 GNMT 在致癌作用和恶性进展中的具体功能知之甚少。为了更好地了解 GNMT 在前列腺癌中的功能，我们使用 siRNA 研究了 GNMT 敲低对细胞增殖和细胞周期的影响。此外，还在 148 例前列腺癌组织中研究了免疫组化 GNMT 表达与临床病理参数之间的关系。在这里，我们表明，siRNA 介导的 GNMT 敲低导致增殖受到抑制，并诱导前列腺癌细胞系中的 G1 期阻滞和细胞凋亡。此外，细胞质中高 GNMT 表达也与更高的 Gleason 评分（P<0.001）和更高的 pT 分期（P=0.027）相关。细胞质中高 GNMT 表达的患者无病生存率明显低于低表达的患者（P<0.001）。在多变量分析中，高细胞质 GNMT 表达对患者无病生存率有显著影响（P=0.005）。这是首次揭示 GNMT 可能通过调节细胞凋亡在促进前列腺癌细胞生长中起重要作用并促进前列腺癌进展的新发现。调节 GNMT 表达或功能可能是开发前列腺癌新型治疗策略的一种方法。GNMT 可能是前列腺癌恶性进展和预后不良的一个新标志物。
