Abstract
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.
Highlights
Melanoma is a highly aggressive and heterogeneous type of cancer, and its incidence is growing faster than any other cancer entity
C-Jun and the tumor suppressor PTEN exhibit a positive correlation in melanoma cells Given that melanomas gain different properties during their progression, we selected six different melanoma cell lines (Sbcl-2, WM3211, WM793, WM1366, WM1158, WM9) categorized by tumor stage (PT, MET) and their previously described BRAF and PTEN mutation status[14]
The detailed molecular mechanism of c-Jun’s influence on melanoma progression and development remains elusive given that only a subset of target genes is known
Summary
Melanoma is a highly aggressive and heterogeneous type of cancer, and its incidence is growing faster than any other cancer entity. Many altered pathways regulating the development and progression of melanoma and the high migratory and invasive potential of melanoma cells have been identified, but a detailed molecular understanding of this disease is largely lacking. The AP-1 family member c-Jun is a main regulator of melanoma progression[4,7,8], acts by regulating target genes supporting proliferation and migration of cancer cells, and promotes the malignant phenotype. Previous chromatin immunoprecipitation (ChIP) studies focusing on AP-1/c-Jun in nonmelanoma cell types identified a few cancer-related target genes of c-Jun. Deregulation of c-Jun is one of the most important events in malignant melanoma and many other cancer entities, but the functional relevance of c-Jun deregulation and its molecular effects on target gene expression have not been determined in detail to date
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
