PDF(Pubmed)
Abstract：
Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5\' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis.
UNASSIGNED: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.
UNASSIGNED: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.
摘要：
在黑色素瘤中优先表达的抗原(PRAME)和10-11易位(TET)双加氧酶介导的5-羟甲基胞嘧啶(5hmC)是新兴的黑色素瘤生物标志物。我们观察到良性痣中PRAME表达与5hmC水平呈负相关，原位黑色素瘤，原发性侵袭性黑色素瘤，和转移性黑色素瘤通过免疫组织化学和多重免疫荧光：痣表现出高5hmC和低PRAME，而黑素瘤表现出相反的模式。黑色素瘤前体的单细胞多重成像显示，减少的5hmC与癌前细胞的PRAME上调一致。对TCGA和GTEx数据库的分析证实了黑色素瘤中TET2和PRAMEmRNA表达之间的负相关。此外,与痣相比，黑色素瘤中PRAME5'启动子的5hmC水平降低，提示5hmC在PRAME转录中的作用。通过TET2过表达恢复5hmC水平显著降低了黑色素瘤细胞系中的PRAME表达。这些发现建立了TET2介导的DNA羟甲基化在调节PRAME表达中的功能，并证明表观遗传重编程在黑色素瘤肿瘤发生中至关重要。
■黑色素瘤生物标志物PRAME表达受TET2介导的DNA羟甲基化的表观遗传负调控。
■黑色素瘤生物标志物PRAME表达受TET2介导的DNA羟甲基化的表观遗传负调控。
