MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET-SOCS1-MMP9 signaling axis.
MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET-SOCS1-MMP9 signaling axis.
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MicroRNA-29a通过TET-SOCS1-MMP9信号轴诱导5-羟甲基胞嘧啶丢失并促进肝细胞癌转移
DOI：
10.1038/cddis.2017.142
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发表时间：
2017-06-29
影响因子：
9
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Chen Q;Yin D;Zhang Y;Yu L;Li XD;Zhou ZJ;Zhou SL;Gao DM;Hu J;Jin C;Wang Z;Shi YH;Cao Y;Fan J;Dai Z;Zhou J
泰特是将5-甲基胞嘧啶（5-mC）转化为5-羟甲基胞嘧啶（5-hmC）的10种转运酶，通过介导DNA去甲基化在生物学和病理学过程中发挥重要作用，然而，这种表观遗传标记及其相关酶在肝细胞癌（HCC）进展中的作用尚不清楚。在这里，我们证明TET家族酶下调是HCC中5-hmC丢失的一个可能机制。我们发现miR-29 a过表达增加细胞因子信号抑制因子1（SOCS 1）启动子的DNA甲基化与肝癌转移相关。此外，miR-29 a通过直接靶向TET家族沉默抗转移SOCS 1，导致SOCS 1启动子去甲基化抑制。染色质免疫沉淀分析证实TET 1通过与SOCS 1的启动子区结合来调节SOCS 1的表达。最后，miR-29 a过表达与HCC患者的不良临床结局和TET-SOCS 1-基质金属蛋白酶（MMP）9轴沉默相关。总之，我们的研究结果表明，5-hmC丢失是HCC的表观遗传标志，miR-29 a是重要的表观遗传修饰剂，通过TET-SOCS 1-MMP 9轴沉默促进HCC转移。这些结果为表观遗传学癌症治疗提供了新的策略。
Ten eleven translocation (TET) enzymes convert 5-methylcytosine (5-mC) to 5-hydroxy-methylcytosine (5-hmC) and have crucial roles in biological and pathological processes by mediating DNA demethylation, however, the functional role of this epigenetic mark and the related enzymes in hepatocellular carcinoma (HCC) progression remains unknown. Here, we demonstrated that TET-family enzymes downregulation was one likely mechanism underlying 5-hmC loss in HCC. We found that miR-29a overexpression increased DNA methylation of suppressor of cytokine signaling 1 (SOCS1) promoter was associated with HCC metastasis in vitro and in vivo. Furthermore, miR-29a silenced anti-metastatic SOCS1 through direct TET-family targeting, resulting in SOCS1 promoter demethylation inhibition. Chromatin immunoprecipitation analyses confirmed that TET1 regulated SOCS1 expression through binding to the promoter region of SOCS1. Finally, miR-29a overexpression correlated with poor clinical outcomes and TET–SOCS1–matrix metalloproteinase (MMP) 9 axis silencing in HCC patients. In conclusion, our findings demonstrate that 5-hmC loss is an epigenetic hallmark of HCC, and miR-29a is an important epigenetic modifier, promoting HCC metastasis through TET–SOCS1–MMP9 axis silencing. The results offer a new strategy for epigenetic cancer therapy.
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影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
30.8
作者：
Langemeijer, Saskia M. C.;Kuiper, Roland P.;Jansen, Joop H.
通讯作者：
Jansen, Joop H.
影响因子：
3.4
作者：
Lin, Li Li;Wang, Wei;Qian, HanGuang
通讯作者：
Qian, HanGuang
影响因子：
14.9
作者：
Griffiths-Jones S;Grocock RJ;van Dongen S;Bateman A;Enright AJ
通讯作者：
Enright AJ
DOI：
10.1126/science.1170116
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tahiliani M;Koh KP;Shen Y;Pastor WA;Bandukwala H;Brudno Y;Agarwal S;Iyer LM;Liu DR;Aravind L;Rao A
通讯作者：
Rao A