Clinically relevant aberrant Filip1l DNA methylation detected in a murine model of cutaneous squamous cell carcinoma.
Clinically relevant aberrant Filip1l DNA methylation detected in a murine model of cutaneous squamous cell carcinoma.
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在皮肤鳞状细胞癌小鼠模型中检测到临床相关的异常 Filip1l DNA 甲基化。
DOI：
10.1016/j.ebiom.2021.103383
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发表时间：
2021-05
期刊：
影响因子：
11.1
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
--
作者：
Roth K;Coussement L;Knatko EV;Higgins M;Steyaert S;Proby CM;de Meyer T;Dinkova-Kostova AT
皮肤鳞状细胞癌(CSCC)是最常见和高度突变的人类恶性肿瘤之一。了解DNA甲基化在CSCC中的影响可能为新的治疗策略提供途径。我们使用还原代表性亚硫酸氢盐测序来分析小鼠CSCC的DNA甲基化。使用LIMMA在CpG水平评估差异甲基化。接下来，我们将其与人类CSCC Infinium的甲基化珠阵数据进行了比较。当基因具有至少一个显著差异甲基化的CPGS(RRBS)/探针(Infinium)，并且在小鼠基因及其人类同源基因中，肿瘤与对照之间至少有30%的差异时，基因被认为具有重大相关性。人类史诗般的Infinium数据被用来区分两种CSCC亚型，干细胞样肿瘤和角质形成细胞样肿瘤。我们发现在小鼠鳞状细胞癌(增加12.8%，p = 0.0011)和干细胞样癌(增加3.1%，p=0.002)中平均甲基化增加，但在人鳞状细胞癌中没有增加(0.2%，p = 0.98)。对差异甲基化基因的比较显示，人类和小鼠的CSCC有惊人的相似之处。小鼠鳞状细胞癌基因座特异性甲基化改变经常发生在潜在的调控功能区域，包括增强子和启动子。一个关键的差异甲基化区域位于肿瘤抑制基因Filip11的潜在增强子中，并且它在小鼠肿瘤中的表达降低。此外，FILIP1L基因在人CSCC中高甲基化，在人CSCC中低表达。DNA甲基化的解除调控是小鼠和人类CSCC的一个重要特征，可能有助于肿瘤抑制基因的沉默，如Filip1所示。英国皮肤基金会，英国癌症研究
Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Understanding the impact of DNA methylation in cSCC may provide avenues for new therapeutic strategies. We used reduced-representation bisulfite sequencing for DNA methylation analysis of murine cSCC. Differential methylation was assessed at the CpG level using limma. Next, we compared with human cSCC Infinium HumanMethylation BeadArray data. Genes were considered to be of major relevance when they featured at least one significantly differentially methylated CpGs (RRBS) / probes (Infinium) with at least a 30% difference between tumour vs. control in both a murine gene and its human orthologue. The human EPIC Infinium data were used to distinguish two cSCC subtypes, stem-cell-like and keratinocyte-like tumours. We found increased average methylation in mouse cSCC (by 12.8%, p = 0.0011) as well as in stem-cell like (by 3.1%, p=0.002), but not keratinocyte-like (0.2%, p = 0.98), human cSCC. Comparison of differentially methylated genes revealed striking similarities between human and mouse cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. A key differentially methylated region was located in a potential enhancer of the tumour suppressor gene Filip1l and its expression was reduced in mouse tumours. Moreover, the FILIP1L locus showed hypermethylation in human cSCC and lower expression in human cSCC cell lines. Deregulation of DNA methylation is an important feature of murine and human cSCC that likely contributes to silencing of tumour suppressor genes, as shown for Filip1l. British Skin Foundation, Cancer Research UK
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
4.6
作者：
Knatko EV;Higgins M;Fahey JW;Dinkova-Kostova AT
通讯作者：
Dinkova-Kostova AT
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1158/1940-6207.capr-14-0362
发表时间：
2015-06
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Knatko EV;Ibbotson SH;Zhang Y;Higgins M;Fahey JW;Talalay P;Dawe RS;Ferguson J;Huang JT;Clarke R;Zheng S;Saito A;Kalra S;Benedict AL;Honda T;Proby CM;Dinkova-Kostova AT
通讯作者：
Dinkova-Kostova AT
影响因子：
9.7
作者：
Dinkova-Kostova, Albena T.;Jenkins, Stephanie N.;Talalay, Paul
通讯作者：
Talalay, Paul