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Xianxin Hua, M.D., Ph.D.

Professor of Cancer Biology
Associate Investigator, Abramson Family Cancer Research Institute
Member, Center for Liver and Digestive Diseases, University of Pennsylvania
Member, Institute of Diabetes, Obesity, and Metabolism (IDOM), University of Pennsylvania
Member, Center for Targeted Therapeutics and Translational Nanomedicine (CT3N), University of Pennsylvania
Member, Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania
Department: Cancer Biology

Contact information
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office: (215) 746-5565
Fax: (215) 746-5525
Lab: (215)746-5566
Hubei Medical College, China, 1983.
Hubei Medical College, China, 1986.
Ph.D. (Cell Regulation)
Department of Molecular Genetics, The University of Texas Southwestern Medical Center at Dallas, Laboratory of Dr. Joseph Goldstein and Dr. Michael Brown, 1995.
Post-Graduate Training
Fellow, Akita University School of Medicine, Japan, 1988-1989.
Research Associate, Oklahoma Medical Research Foundation, 1989-1991.
Postdoctoral Fellow and Clinical Scientist, Laboratory of Dr. Harvey Lodish , Whitehead Institute, MIT, 1996-2000.
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Description of Research Expertise

Research Interests

1) The critical role of the tumor suppressor, Menin, in epigenetic regulation of gene transcription, cell signaling, cell proliferation, and the underlying mechanisms; suppression of neuroendocrine/carcinoid tumors by targeting menin-regulated pathways
2) The interplay of Menin, MLL methyltransferase, and oncogenic MLL fusion proteins in promoting leukemogenesis
3) Reversal of diabetes by inhibiting menin
4) Signal transduction mediated by transforming growth factor beta (TGF-ß) and menin.

Key words: Menin, Men1, epigenetics, MLL, histone methyltransferase, leukemia, neuroendocrine tumors, diabetes, and TGF-ß signaling.

Description of Research

Our research focuses on elucidating the molecular mechanisms whereby menin, a scaffold protein interacting with multiple epigenetic regulators, regulates 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.

Rotation Projects
1. To identify potentially functional post-translational modifications of menin
2. To investigate how Men1 excision de-represses multiple pro-proliferative genes and upregulates beta cell proliferation
3. To identify functional and epigenetic partners of menin that control leukemogenesis or neuroendocrine tumors.

Lab personnel:
Ashley Banks, Administrative Assistant (asbanks@mail.med.upenn.edu)
Brian Bakke, Research Specialist and Lab Manager
Buddha Gurung, Research Fellow
Xin He, Postdoctoral Researcher
Bryson Katona, Gastroenterology Fellow
Xiangchen Kong, Postdoctoral Researcher
Smita Matkar, Research Associate
Abdul Bari Muhammad, Postdoctoral Fellow
Kate Szigety, MD/PhD Graduate Rotation Student
Haoren Wang, Research Specialist
Lei Wang, Visiting Graduate Student

Selected Publications

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.

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.

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.

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.

Austin T. Thiel, Zijie Feng, Dhruv K. Pant, Lewis A. Chodosh 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.

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.

Jing Huang, Buddha Gurung, Bingbing Wan, Smita Matkar, Natalia A. Veniaminova, Ke Wan, Juanita L. Merchant, Xianxin Hua*, and Ming Lei* (*co-corresponding author): The same pocket in menin binds both MLL and JunD, but oppositely regulates transcription. Nature 432(7386): 542-6, 2012.

Yang, Y., Gurung, B., Wu, T., Wang, H., Stoffers, D. A. 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.

Thiel, A.T., 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.

Yuqing Yang, Haoren Wang, and Xianxin Hua: Deletion of the Men1 gene prevents streptozotocin-induced hyperglycemia in mice. Exp Diabetes Res. 2010 2010.

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Last updated: 10/16/2015
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