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Epigenetic regulations in alternative telomere lengthening: Understanding the mechanistic insight in arsenic-induced skin cancer patients.

替代端粒延长中的表观遗传调节: 了解砷诱导皮肤癌患者的机制见解。

  • 影响因子:5.92
  • DOI:10.1016/j.scitotenv.2019.135388
  • 作者列表:"Bhattacharjee P","Das A","Giri AK","Bhattacharjee P
  • 发表时间:2020-02-20
Abstract

:Telomere integrity is considered to be one of the primary mechanisms during malignant transformation. Arsenic, a group 1 carcinogenic metalloid, has been reported to cause telomere lengthening in a telomerase-independent manner. Recent studies suggest a significant role for epigenetic modifications in regulating telomeric length and integrity. Here, we have explored the role of epigenetic deregulation in alternative lengthening of telomeres (ALT) in arsenic-exposed skin cancer tissues and corresponding non-tumor tissues. The relative telomere length (RTL) was analyzed by qRT-PCR using 2-ΔΔCt method. The subtelomeric methylation pattern of the four chromosomes (7q, 18p, 21q and XpYp) were analysed by Methylation Specific PCR (MSP) in 40 pairs of arsenic exposed skin cancer tissues and its corresponding control. The role of constitutive heterochromatin histone marks in the regulation of telomere length (TL) was analyzed by targeted ELISA. A 2-fold increase of relative telomere length in 85% of the arsenic-induced skin cancer tissues was observed. Among the four chromosomes, subtelomere of XpYp was found to be hypermethylated (p < 0.001) whereas 18p was hypomethylated (p < 0.01). Additionally, the level of H4K20me3, a heterochromatic mark was found to be significantly down-regulated (p < 0.0003), and inversely correlated with telomere length indicating loss of heterochromatinization of telomeric DNA. These observations highlight the novel role of epigenetic regulation in the maintenance of constitutive heterochromatin structure at telomere. Alteration in subtelomeric DNA methylation patterns and depletion of H4K20me3 might lead to loss of heterochromatinization resulting in arsenic-induced telomeric elongation. We provide novel data indicating possible alternative determinants of telomere elongation through epigenetic modifications during arsenic-induced skin carcinogenesis which could be used as early 'epimarkers' in the near future. The findings provide new insights about the mechanism of arsenic-induced carcinogenesis.

摘要

: 端粒完整性被认为是恶性转化过程中的主要机制之一。砷,一组 1 致癌类金属,已被报道以非端粒酶依赖性方式引起端粒延长。最近的研究表明表观遗传修饰在调节端粒长度和完整性方面具有重要作用。在此,我们探讨了表观遗传失调在砷暴露皮肤癌组织和相应非肿瘤组织端粒 (ALT) 替代延长中的作用。使用 2 Δ Δ ct法通过qRT-PCR分析相对端粒长度 (RTL)。通过甲基化特异性PCR (MSP) 分析 4 条染色体 (7q、 18p、 21q和XpYp) 的亚端粒甲基化模式 40 对砷暴露皮肤癌组织及其相应对照。通过靶向ELISA分析组成性异染色质组蛋白标记在端粒长度 (TL) 调控中的作用。在 85% 的砷诱导的皮肤癌组织中观察到相对端粒长度增加 2 倍。在 4 条染色体中,XpYp的亚端粒被发现是高甲基化的 (p <0.001),而 18p是低甲基化的 (p <0.01)。此外,发现异色标记H4K20me3 的水平显著下调 (p <0.0003),并与端粒长度呈负相关,表明端粒DNA的异色化丢失。这些观察结果强调了表观遗传调控在维持端粒组成性异染色质结构中的新作用。亚端粒DNA甲基化模式的改变和H4K20me3 的耗竭可能导致异色化的丧失,导致砷诱导的端粒延长。我们提供了新的数据,表明在砷诱导的皮肤癌变过程中,通过表观遗传修饰可能导致端粒延长的替代决定因素,这可能在不久的将来被用作早期的 “epimark”。这些发现为砷致癌机制提供了新的见解。

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影响因子:2.93
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DOI:10.1016/j.jaad.2019.04.067
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影响因子:0.96
发表时间:2020-01-01
DOI:10.1097/DAD.0000000000001459
作者列表:["Lang UE","Love NR","Cheung C","McCalmont TH","Kim J"]

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皮肤肿瘤方向

皮肤肿瘤是发生在皮肤的细胞增生性疾病,是一种常见病。发生于皮内或皮下组织的新生物,种类很多,临床上分良性肿瘤和恶性肿瘤。恶性肿瘤可以不断增殖,引起转移,威胁生命,称为皮肤癌。

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