Institute of Biochemistry (Emil-Fischer Center), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Faculty of Applied Health Care Sciences, University of Applied Science, Deggendorf, Germany.
Cell Death Dis. 2019 Aug 5;10(8):584. doi: 10.1038/s41419-019-1821-9.
Due to the critical impact of active AP-1 transcription factors in melanoma, it is important to define their target genes and to identify and ultimately inhibit oncogenic signals. Here we mapped the genome-wide occupancy of the AP-1 family member c-Jun in different melanoma cells and correlated AP-1 binding with transcriptome data to detect genes in melanoma regulated by c-Jun. Our analysis shows that c-Jun supports the malignant phenotype by deregulating genes in cancer-relevant signaling pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. Moreover, we demonstrate that the importance of c-Jun depends on melanoma stage and mutation status of the tumor suppressor PTEN. Our study reveals that activation of c-Jun overrules the tumor suppressive effect of PTEN in early melanoma development. These findings help to understand the relevance of c-Jun within cancer pathways in different melanoma cell types, especially in relation to MAPK and PI3K pathways, which are commonly deregulated in melanomas. Consequently, targeting c-Jun in PTEN melanoma cells may represent a promising therapeutic strategy to inhibit survival of melanoma cells to prevent the development of a metastatic phenotype.
由于活性 AP-1 转录因子在黑色素瘤中的关键影响，确定其靶基因并识别和最终抑制致癌信号非常重要。在这里，我们绘制了不同黑色素瘤细胞中 AP-1 家族成员 c-Jun 的全基因组占据图谱，并将 AP-1 结合与转录组数据相关联，以检测黑色素瘤中受 c-Jun 调控的基因。我们的分析表明，c-Jun 通过调节丝裂原活化蛋白激酶 (MAPK) 和磷脂酰肌醇-3-激酶 (PI3K) 等与癌症相关的信号通路中的基因，支持恶性表型。此外，我们证明 c-Jun 的重要性取决于黑色素瘤的阶段和肿瘤抑制因子 PTEN 的突变状态。我们的研究表明，c-Jun 的激活在早期黑色素瘤发展中推翻了 PTEN 的肿瘤抑制作用。这些发现有助于理解不同黑色素瘤细胞类型中 c-Jun 在癌症途径中的相关性，特别是与 MAPK 和 PI3K 途径的相关性，这些途径在黑色素瘤中经常失调。因此，针对 PTEN 黑色素瘤细胞中的 c-Jun 可能代表一种有前途的治疗策略，以抑制黑色素瘤细胞的存活，防止转移表型的发展。
