Laboratory of Epigenetics, Cancer Research Institute and Brain Korea 2nd Stage, Seoul National University College of Medicine, Seoul, Republic of Korea.
Am J Pathol. 2013 Apr;182(4):1275-85. doi: 10.1016/j.ajpath.2013.01.004. Epub 2013 Feb 10.
Dual-specificity phosphatase 5 (DUSP5), which regulates the duration and magnitude of ERK1/2 phosphoactivation within the mitogen-activated protein kinase (MAPK) cascade, has recently been proposed to be a tumor suppressor. However, the epigenetic regulation of DUSP5 and its critical roles in gastric cancer (GC) remain unknown. We compared differential RNA expression profiles of GC cell lines with or without treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine. DUSP5 expression was dramatically decreased by DNA methylation. Hypermethylation of the DUSP5 promoter was detected in GC tissue samples, but not in normal healthy gastric mucosa samples. Restoring DUSP5 expression in DUSP5-silenced GC cell lines decreased their growth and colony-forming ability by causing arrest in the transition from G1 to S phase in the cell cycle as a result of dephosphorylation of ERK1/2 in the nucleus. Moreover, in a set of surgically resected GC cases (n = 179), GCs with DUSP5 promoter region hypermethylation (30.2%) exhibited significantly shortened survival, compared with GCs without DUSP5 methylation (P = 0.009). These results suggest that silencing of DUSP5 by promoter hypermethylation causes increased maintenance of phosphorylated ERK1/2, driving cell proliferation and contributing to gastric carcinogenesis. Furthermore, DUSP5 methylation may serve as a prognostic marker for GC, but this requires validation in a larger set of GC samples.
双特异性磷酸酶 5（DUSP5）可调节丝裂原活化蛋白激酶（MAPK）级联中 ERK1/2 磷酸化的持续时间和幅度，最近被认为是一种肿瘤抑制因子。然而，DUSP5 的表观遗传调控及其在胃癌（GC）中的关键作用尚不清楚。我们比较了经 DNA 去甲基化剂 5-氮杂-2'-脱氧胞苷处理或未处理的 GC 细胞系的差异 RNA 表达谱。DUSP5 的表达被 DNA 甲基化显著下调。在 GC 组织样本中检测到 DUSP5 启动子的高甲基化，但在正常健康胃黏膜样本中未检测到。在 DUSP5 沉默的 GC 细胞系中恢复 DUSP5 表达，通过核内 ERK1/2 的去磷酸化，导致细胞周期从 G1 期向 S 期的过渡受阻，从而降低其生长和集落形成能力。此外，在一组手术切除的 GC 病例（n = 179）中，与没有 DUSP5 甲基化的 GC 相比，DUSP5 启动子区域高甲基化（30.2%）的 GC 表现出明显缩短的生存时间（P = 0.009）。这些结果表明，启动子高甲基化导致 DUSP5 沉默，从而增加磷酸化 ERK1/2 的维持，促进细胞增殖，并有助于胃癌发生。此外，DUSP5 甲基化可能是 GC 的预后标志物，但这需要在更大的 GC 样本中进行验证。
