在抑癌基因啟動子的CpG島群上?發生??正常的過?甲基化時，往往導致人?癌症的發生及進程。負責將CpG島群甲基化的是DNA甲基轉移酵素（5'-cytosine-methyltransferase，簡稱DNMT）。抑制形成CpG島群的甲基化的藥物正可以作為恢?抑癌基因的表現及活化癌細胞中抑制癌症的重要?徑的新穎標的。而Mithramycin A（簡稱MMA）是一個會與富含GC及CG序?的DNA結合的藥物，因此本研究檢測癌細胞在經過MMA的處?之後，是否會抑制CpG島群甲基化的情形。我們發現當以低劑?(10 nM)的MMA處?癌細胞14天後，會減少SLIT2基因的CpG島群過?甲基化的情形，並進而使這個具有抑制癌細胞轉移的SLIT2重現基因表達。同時間藉由膜穿透(transwell)實驗我們也發現MMA可?低具有高轉移能?的癌細胞CL1-5的穿越及移動能?。為?暸解MMA的作用途徑，我們使用西方點漬法發現MMA會使DNMT1蛋白明顯下?，但是DNMT1的基因表現?受影響。總結研究結果發現，MMA具有去DNA甲基化及抑制癌細胞轉移的潛?。而抑制的機轉可能藉由?低癌細胞中DNMT1的蛋白表達?，進而導致抑制癌細胞轉移的基因啟動子去甲基化且重新恢?表達。

Abnormal CpG island hypermethylation of multiple tumor suppressor genes (TSGs) can lead to the initiation and progression of human cancer. The cytosine of the CpG island on promoter region is methylated by 5'-cytosine-methyltransferases (DNMTs). Pharmacologic inhibitors of CpG island methylation provide a rational approach to reactivate the TSGs in tumor cells and restoring of critical cellular pathways in cancer cells. Mithramycin A (MMA) is known to be a GC and CG-rich DNA binding agent. We sought to determine whether MMA could inhibit CpG island methylation and DNMT expression in lung cancer cells. We found that MMA reduced CpG island methylation of anti-metastasis TSGs, SLIT2, which associated with the prevention of metastasis. When highly metastatic CL1-5 lung cancer cells were treated with low does (10 nM) of MMA for 14 days, they re-expressed mRNA levels for SLIT2 genes. MMA also inhibited the invasion phenotypes of CL1-5 cells as indicated by its inhibition of cancer cell migration using transwell assays. Western blots showed that DNMT1 protein levels were depleted after MMA. These data support the idea that MMA has demethylation and anti-metastasis effects on lung cancer cells. This inhibitory mechanism of MMA in DNA methylation may be mediated by the depletion of DNMT1 protein.