Epigenetic reprogramming of melanoma cells by vitamin C treatment.
Epigenetic reprogramming of melanoma cells by vitamin C treatment.
复制标题
通过维生素C治疗对黑色素瘤细胞的表观遗传重编程。
DOI：
10.1186/s13148-015-0087-z
复制
发表时间：
2015
影响因子：
5.7
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Gustafson CB;Yang C;Dickson KM;Shao H;Van Booven D;Harbour JW;Liu ZJ;Wang G
5-羟甲基胞嘧啶（5hmC）的缺失已被确定为黑色素瘤的一种新的表观遗传标志。5hmC缺失的已知机制之一是10 - 11易位家族双加氧酶（TET）基因的表达减少，该基因编码催化5hmC生成的酶。研究表明，过表达TET2可以部分重建黑色素瘤中正常的5hmC谱，并降低啮齿动物的侵袭性。然而，在患者中过表达TETs的可行性尚不清楚。我们和其他人最近已经证明，TETs需要维生素C作为辅助因子来产生5hmC。这一发现促使我们测试维生素C作为过表达TETs的替代品，是否可以重建黑色素瘤中5hmC的含量。与之前的报道一致，我们发现TETs的表达在各种黑色素瘤细胞系中下降。相反，钠依赖性维生素C转运蛋白（svct）的表达在黑色素瘤转移细胞系中下调。生理水平（0.1 mM）的维生素C处理可促进不同阶段黑色素瘤细胞系中5hmC的含量向健康黑色素细胞水平靠拢，这与过表达TET2的效果相当。维生素C处理通过抑制转移性A2058细胞的迁移和不依赖于锚定的生长来降低其恶性程度，而对增殖率没有任何影响。此外，维生素C处理引起RNA-seq显示的全基因组转录的改变，主要是在ArhGAP30和参与细胞外基质重塑的基因中，这可能是恶性表型减少的基础。我们的数据支持维生素C处理增加黑色素瘤细胞中5hmC含量的观点，同时导致软琼脂中肿瘤细胞侵袭性和克隆性生长的降低。因此，维生素C可能是黑色素瘤的潜在表观遗传治疗方法。
The loss of 5-hydroxymethylcytosine (5hmC) has been identified as a novel epigenetic hallmark for melanoma. One of the known mechanisms underlying the loss of 5hmC is the decrease in expression of ten-eleven translocation family dioxygenase (TET) genes, which encode enzymes that catalyze the generation of 5hmC. Overexpressing TET2 was shown to partially reestablish a normal 5hmC profile in melanoma and decrease invasiveness in rodents. However, the feasibility to overexpress TETs in patients remains unclear. We and others have recently demonstrated that TETs require vitamin C as a cofactor to generate 5hmC. This finding prompted us to test whether vitamin C, as an alternative to overexpressing TETs, could rebuild 5hmC content in melanoma. Consistent with previous reports, we found that the expression of TETs was decreased in various melanoma cell lines. In contrast, the expressions of sodium-dependent vitamin C transporters (SVCTs) were down-regulated in cell lines derived from melanoma metastases. Treatment of vitamin C at the physiological level (0.1 mM) promoted the content of 5hmC in melanoma cell lines derived from different stages toward the level of healthy melanocytes, which was comparable to the effect of overexpressing TET2. Vitamin C treatment decreased the malignancy of metastatic A2058 cells by inhibiting migration and anchorage-independent growth, while not exerting any effect on the rate of proliferation. Further, vitamin C treatment caused alterations in genome-wide transcriptions shown by RNA-seq, predominantly in ArhGAP30 and genes involved in extracellular matrix remodeling, which could underlie the decreased malignant phenotypes. Our data support the idea that vitamin C treatment increases 5hmC content in melanoma cells, while causing a decrease in tumor-cell invasiveness and clonogenic growth in soft agar. Thus, vitamin C could be a potential epigenetic treatment for melanoma.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
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：
15.9
作者：
Balint, K;Xiao, M;Liu, ZJ
通讯作者：
Liu, ZJ
影响因子：
64.5
作者：
Mellen, Marian;Ayata, Pinar;Heintz, Nathaniel
通讯作者：
Heintz, Nathaniel