Our research focuses on elucidating the molecular mechanisms whereby menin-mediated epigenetic mechanisms in regulating endocrine cells including pancreatic beta cells, endocrine tumors, and MLL fusion protein-induced leukemia. In particular, we are interested in dissecting the function of menin, which is mutated in hereditary human tumor syndrome, Multiple Endocrine Neoplasia Type 1 (MEN1), in repressing beta cells and endocrine tumors and in promoting leukemogenesis.
1. We seek to elucidate how Menin suppresses endocrine cells, such as pancreatic beta cells, via regulating histone methylations and expression of pro-proliferative genes. We are also interested in identifying menin-regulated key pathways that can be suppressed to inhibit neuroendocrine tumors.
2. Determining how menin, which acts as a tumor promoter in MLL fusion protein-induced leukemia, cooperates with wild-type MLL protein to promote leukemia and how the menin and wt MLL axis can be suppressed to improve therapy for this aggressive leukemia.
3. Understanding how inhibition of menin leads to reversal of established diabetes in mouse models and determining whether the menin pathway could be explored to ameliorate diabetes.
4. Investigating the interplay between menin, post-transcriptional modifications of menin, and TGF-ß signaling in repressing pancreatic beta cells. As both menin and TGF-ß inhibit cell proliferation, we will test whether menin and TGF-ß cooperate to suppress beta cell proliferation and the underlying mechanisms, using biochemical studies and mouse models.
These comprehensive approaches will provide novel insights into the molecular mechanisms for MEN1 tumorigenesis, regulation of beta cells, and leukemogenesis, shedding light on improving therapy against neuroendocrine tumors, leukemia, and diabetes.
The Hua Laboratory
The research team of Xianxin Hua, Ph.D., seeks to understand how epigenetic regulations, especially those mediated by menin, control development of a variety of diseases, such as endocrine tumors, leukemia, and diabetes. His group has discovered that menin may act as a scaffold protein or a node to interact with various epigenetic regulators to control expression of genes that modulate cell proliferation and survival. They are elucidating how a cascade of the menin-mediated regulatory step is controlled at the molecular level, using a variety of approaches involving molecular and cell biology, genetics, and mouse models. They seek to help improve the treatment of the diseases by targeting the novel molecular steps.
01.Matkar S, Sharma P, Gao S, Gurung B, Katona BW, Liao J, Muhammad AB, Kong XC, Wang L, Jin G, Dang CV, Hua X: An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis. Cancer Cell 28(4): 472-85, Oct 2015.
02. Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL: Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525(7568): 206-11, Sep 2015.
03. Matkar S, Katona BW, Hua X: Harnessing the Hidden Antitumor Power of the MLL-AF4 Oncogene to Fight Leukemia. Cancer Cell 25(4): 411-3, Apr 2014.
04. Matkar S, Thiel A, and Hua X: Menin: a scaffold protein that controls gene transcription and cell signaling. Trends in Biochemical Sciences (TIBS) 38(8): 394-402, Aug 2013.
05. Thiel AT, Feng Z, Pant DK, Chodosh LA and Hua X: The Trithorax Protein Partner Menin Acts in Tandem with EZH2 to Suppress C/EBPa and Differentiation in MLL-AF9 Leukemia. Haematologica 98(6): 918, Jun 2013.
06. Gurung B, Feng Z, Iwamoto DV, Thiel A, Jin G, Fan C-M, Ng JM, Curran T, Hua X: Menin Epigenetically Represses Hedgehog signaling in MEN1 Tumor Syndrome Cancer Research 73(8): 2650-8, Apr 2013.
07. Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X*, and Lei M* (*co-corresponding author) The same pocket in menin binds both MLL and JunD, but oppositely regulates transcription. Nature 432(7386): 542-6, 2012.
08. Yang Y, Gurung B, Wu T, Wang H, Stoffers DA, and Hua X: Reversal of pre-existing hyperglycemia in diabetic mice by acute deletion of Men1. Proc Natl Acad Sci USA 107(47): 20358-63, Nov 2010.
10. Yang Y, Wang H, and Hua X: Deletion of the Men1 gene prevents streptozotocin-induced hyperglycemia in mice. Exp Diabetes Res. 2010; 2010: 876701.
Thiel AT, Blessington P, Zou T, Feather D, Wu X, Zhang H, Liu L, Koretzky G, Ernst P, and Hua X: MLL-AF9-induced leukemic transformation requires co-expression of wild type MLL allele. Cancer Cell 17: 148-159, 2010. Notes: The work was featured on the cover of this issue of Cancer Cell.
Abdul Bari Muhammad - Postdoctoral Fellow
Brian Bakke - Research Specialist and Lab Manager
Bryson Katona - Gastroenterology Fellow
Buddha Gurung - Research Fellow
Haoren Wang - Research Specialist
Kate Szigety - MD/PhD Graduate Rotation Student
Lei Wang - Visiting Graduate Student
Smita Matkar - Research Associate
Xiangchen Kong - Postdoctoral Researcher
Xin He - Postdoctoral Researcher
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