Abstract
Abstract While a germline heterozygous mutation in the Multiple Endocrine Neoplasia type 1 (MEN1) gene predisposes tumor formation in specific tissues such as the endocrine pancreas, parathyroid glands and anterior pituitary, this tissue-specific tumorigenesis is not dependent on MEN1 mutations alone. In fact, a homozygous deletion of Men1 in mouse pancreatic exocrine tissue does not result in tumor formation, suggesting a tissue-specific mechanism. Loss of menin activates a menin-interacting protein retinoblastoma-binding-protein 5 (RBBP5). Since RBBP5 transcriptionally regulates DNA methyltransferase 1 (DNMT1), this causes global DNA hypermethylation and subsequent tumorigenesis in MEN1-target endocrine tissues. We hypothesize that while RBBP5 is ubiquitously expressed, it exclusively binds to the DNMT1 promoter in MEN1-target-tissues through its recruitment by tissue-specific factors. Using chromatin immunoprecipitation, we demonstrated that Rbbp5 is bound to the Dnmt1 promoter in MEN1-target-tissues, while not in non-target tissues. Following a high-throughput genome-wide approach, we identified two candidate factors that may recruit Rbbp5 to the Dnmt1 promoter. Immunohistochemistry showed MEN1-target-tissue-specific expression of these target factors. Co-immunoprecipitation revealed MEN1-target-tissue-specific binding of Rbbp5 to the factors. In conclusion, Rbbp5 binds the Dnmt1 promoter in MEN1-target-tissues and we have identified candidates for Rbbp5 recruitment to the Dnmt1 promoter that must be tested further to determine their role in the observed tissue specificity of MEN1-related tumorigenesis. Citation Format: Juliet C. Gardiner, Steven K. Libutti. Tissue-specific tumorigenesis in multiple endocrine neoplasia type I [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2080.
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