1. Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation
- Author
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Zeng, Hanlin, Jorapur, Aparna, Shain, A Hunter, Lang, Ursula E, Torres, Rodrigo, Zhang, Yuntian, McNeal, Andrew S, Botton, Thomas, Lin, Jue, Donne, Matthew, Bastian, Ingmar N, Yu, Richard, North, Jeffrey P, Pincus, Laura, Ruben, Beth S, Joseph, Nancy M, Yeh, Iwei, Bastian, Boris C, and Judson, Robert L
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Cell Line ,Tumor ,Cell Movement ,Cyclin-Dependent Kinase Inhibitor p16 ,E2F1 Transcription Factor ,Female ,Gene Expression Regulation ,Neoplastic ,Homeodomain Proteins ,Humans ,Loss of Heterozygosity ,Lung Neoplasms ,Male ,Melanocytes ,Melanoma ,Mice ,Inbred NOD ,Neoplasm Invasiveness ,POU Domain Factors ,Point Mutation ,Proto-Oncogene Proteins B-raf ,Signal Transduction ,Skin Neoplasms ,Transcriptional Activation ,BRN2 ,CDKN2A ,CRISPR engineering ,E2F1 ,invasion ,melanocytes ,melanoma ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.
- Published
- 2018