The methionine salvage pathway-involving ADI1 inhibits hepatoma growth by epigenetically altering genes expression via elevating S-adenosylmethionine
The methionine salvage pathway-involving ADI1 inhibits hepatoma growth by epigenetically altering genes expression via elevating S-adenosylmethionine
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DOI：
10.1038/s41419-019-1486-4
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发表时间：
2019-03-11
影响因子：
9
通讯作者：
Yeh, Chau-Ting
中科院分区：
文献类型：
--
作者：
Chu, Yu-De;Lai, Hsin-Yu;Yeh, Chau-Ting
参与5 '-甲硫腺苷（MTA）循环的人酸还原酮双加氧酶1（ADI 1）被认为是前列腺癌的肿瘤抑制因子，但其在肝细胞癌（HCC）中的作用尚不清楚。在这里，我们证明了在HCC组织中ADI 1在蛋白或mRNA水平上的显著降低。此外，较高的ADI 1水平与HCC患者术后无复发生存率相关。通过改变肝癌细胞中ADI 1的表达，观察到ADI 1与细胞增殖之间的负相关性。通过使用过表达在金属结合位点（分别为E94 A和H133 A）携带突变的ADI 1突变体的细胞进行基于细胞的和异种移植物实验，所述突变体选择性地破坏差异催化步骤，导致停留或离开MTA循环。结果表明，生长抑制作用是通过促进MTA循环介导的。cDNA微阵列分析，随后验证实验确定，窖蛋白-1（CAV 1），在肝癌中的生长促进蛋白，ADI 1过表达后显着下降。S-腺苷甲硫氨酸（SAMe）水平的增加介导的CAV 1表达的抑制。在ADI 1过表达时，CAV 1启动子的甲基化状态发生显著改变。最后，全基因组甲基化分析显示，ADI 1过表达改变了一组癌症相关基因的启动子甲基化谱，包括CAV 1和编码反义非编码RNA、长非编码RNA和microRNA的基因，导致其表达水平的显著变化。总之，ADI 1表达促进MTA周期以增加SAMe水平，这改变了全基因组启动子甲基化谱，导致基因表达改变和HCC生长抑制。
The 5'-methylthioadenosine (MTA) cycle-participating human acireductone dioxygenase 1 (ADI1) has been implicated as a tumor suppressor in prostate cancer, yet its role remains unclear in hepatocellular carcinoma (HCC). Here, we demonstrated a significant reduction of ADI1, either in protein or mRNA level, in HCC tissues. Additionally, higher ADI1 levels were associated with favorable postoperative recurrence-free survival in HCC patients. By altering ADI1 expression in HCC cells, a negative correlation between ADI1 and cell proliferation was observed. Cell-based and xenograft experiments were performed by using cells overexpressing ADI1 mutants carrying mutations at the metal-binding sites (E94A and H133A, respectively), which selectively disrupted differential catalytic steps, resulting in staying or leaving the MTA cycle. The results showed that the growth suppression effect was mediated by accelerating the MTA cycle. A cDNA microarray analysis followed by verification experiments identified that caveolin-1 (CAV1), a growth-promoting protein in HCC, was markedly decreased upon ADI1 overexpression. Suppression of CAV1 expression was mediated by an increase of S-adenosylmethionine (SAMe) level. The methylation status of CAV1 promoter was significantly altered upon ADI1 overexpression. Finally, a genome-wide methylation analysis revealed that ADI1 overexpression altered promoter methylation profiles in a set of cancer-related genes, including CAV1 and genes encoding antisense non-coding RNAs, long non-coding RNAs, and microRNAs, resulting in significant changes of their expression levels. In conclusion, ADI1 expression promoted MTA cycle to increase SAMe levels, which altered genome-wide promoter methylation profiles, resulting in altered gene expression and HCC growth suppression.