Germline mutations in the MEN1 gene encoding menin predispose to endocrine tumors mainly of the parathyroids, anterior pituitary and entero-pancreatic endocrine tissues. We have investigated the molecular basis of this tissue specific tumorigenesis from menin loss in the pathogenesis of tumors of the pancreatic islet β-cells (insulinoma). It is possible that the cause of the tissue-specificity is due to menin-mediated regulation of one or more tissue-specific factors such as those that control differentiation during embryogenesis. Therefore, we assessed the effect of menin loss or gain on the expression of factors that are known to control β-cell differentiation. We found that the β-cell differentiation factor HLXB9 (Mnx-1) is post-transcriptionally upregulated upon menin loss. HLXB9 causes apoptosis in the presence of menin, in MIN6 insulinoma β-cells. Thus, dysregulation of HLXB9 predicts a possible mechanism for β-cell proliferation in insulinomas resulting from the possible blockade of the pro-apoptotic activity of HLXB9 upon menin loss. These findings advance the understanding of how a ubiquitously expressed protein such as menin controls tissue-specific tumorigenesis. Moreover, our data reveal the mechanisms of action of HLXB9 and its targets in β-cells. We also showed that HLXB9 is phosphorylated by the kinase GSK-3β, both phospho-HLXB9 and GSK-3β are expressed in mouse and human β-cell tumors, and GSK-3β inhibitors (such as lithium chloride) reduced cell proliferation and delayed cell cycle progression of mouse β-cell tumor cell lines. We are interested in exploring whether lithium chloride treatment in the mouse model of MEN1 would reduce endocrine tumorigenesis. We are currently investigating the role of HLXB9 in sporadic pancreatic endocrine tumors, and the molecular mechanisms by which phospho-HLXB9 promotes tumorigenesis. These studies will provide insights into the pathways and actions of HLXB9 and its targets in normal β-cells and in β-cell tumors.

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3
Fiscal Year
2015
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U.S. National Inst Diabetes/Digst/Kidney
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Kharade, Sampada S; Parekh, Vaishali I; Agarwal, Sunita K (2018) Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO. Endocrinology 159:1199-1212
Iyer, Sucharitha; Agarwal, Sunita K (2018) Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types. J Mol Endocrinol 61:R13-R24
Keutgen, Xavier M; Kumar, Suresh; Gara, Sudheer et al. (2018) Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype. Cancer 124:636-647
Iyer, Sucharitha; Modali, Sita D; Agarwal, Sunita K (2017) Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells. Mol Cell Biol 37:
Desai, Shruti S; Kharade, Sampada S; Parekh, Vaishali I et al. (2015) Pro-oncogenic Roles of HLXB9 Protein in Insulinoma Cells through Interaction with Nono Protein and Down-regulation of the c-Met Inhibitor Cblb (Casitas B-lineage Lymphoma b). J Biol Chem 290:25595-608
Agarwal, Sunita K (2014) Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies. Int J Endocr Oncol 1:153-161
Desai, Shruti S; Modali, Sita D; Parekh, Vaishali I et al. (2014) GSK-3? protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation. J Biol Chem 289:5386-98
Debelenko, Larisa V; Agarwal, Sunita; Du, Qiang et al. (2014) Menin immunoreactivity in secretory granules of human pancreatic islet cells. Appl Immunohistochem Mol Morphol 22:748-55