Role of ATRX/DAXX/H3.3 Chromatin Regulation in Pancreatic NETs

Year: 2017
Institution: The University of Texas Southwestern Medical Center (UT Southwestern)
Country: United States
State: TX
Award Type: NETRF GRANTS 2005-2017
NET Type: Pancreas
Science Type: Basic

General Description

Multiple Endocrine Neoplasia type I (MEN1) is a hereditary tumor syndrome including neuroendocrine tumors in several endocrine organs.  Dr. Xianxin Hua’s group has discovered that a menin mutation leads to an increase in Hedgehog signaling, a pro-proliferative and tumor-related pathway, via repression of a protein, PRMT5. Importantly, pharmacologic inhibition of Hedgehog signaling inhibits tumor cell growth. These findings thus uncover a new link between menin and Hedgehog signaling, and pave the way to conduct clinical trials to treat the neuroendocrine tumors using an already FDA approved drug.Dr. Hua’s lab has expertise in studying the function of oncogenes and tumor suppressor genes, including menin, a protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. Patients with MEN1 syndrome have a mutation in the MEN1 gene.

Dr. Hua’s lab has found that menin appears to suppress a pro-proliferative signaling pathway via protein methylation. Because menin mutations are linked to pancreatic neuroendocrine tumors, his findings suggest that targeting the menin-regulated signaling pathway may be crucial for treating neuroendocrine tumors. This goal of this project is to unravel the crucial role of the menin-regulated cascade in the maintenance of neuroendocrine tumors, underscoring the pathway as an important target for therapy. By studying menin Dr. Hua seeks to uncover a new treatment strategy for patients with neuroendocrine tumors.

Publications

Feng Z, Wang L, Sun Y, Jiang Z, Domsic J,  An C, Xing B, Tian J, Liu X, Metz DC,  Xiaolu L,  Yang X,  Marmorstein R, Ma X, Hua X.  Menin and Daxx interact to block neuroendocrine tumors through epigenetic control of the membrane metalloendopeptidase MME.  Cancer Res. 2017 Jan 15; 77(2): 401–411. Published online 2016 Nov 21. doi: 10.1158/00085472.

Feng Z, Ma J, Hua X. Epigenetic regulation by the menin pathway. Endocr Relat Cancer. 2017;24(10):T147-T159. doi: 10.1530/ERC-17-0298

He X,  Wang L, Yan J, Yuan C, Witze ES, Hua X. Menin localization in cell membrane compartment. Cancer Biol Ther. 2016 Jan; 17(1): 114–122. Published online 2015 Nov 11. doi: 10.1080/15384047.2015.1108497.

Gurung B, Katona BW, Hua X. Menin-mediated regulation of miRNA biogenesis uncovers the IRS2 pathway as a target for regulating pancreatic beta cells. Oncoscience. 2014;1(9):562-6. Published 2014 Sep 15. doi:10.18632/oncoscience.79

Gurung B, Muhammad AB, Hua X. Menin is required for optimal processing of the microRNA let-7a. J Biol Chem. 2014;289(14):9902-8.doi: 10.1074/jbc.M113.520692

Gurung B, Feng Z, Hua X. Menin directly represses Gli1 expression independent of canonical Hedgehog signaling. Mol Cancer Res. 2013;11(10):1215-22.  doi: 10.1158/1541-7786.MCR-13-0170

Gurung B, Feng Z, Iwamoto DV, et al. Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome. Cancer Res. 2013;73(8):2650-8. doi: 10.1158/0008-5472.CAN-12-3158

Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013;38(8):394-402.  doi: 10.1016/j.tibs.2013.05.005

Gurung B, Hua X. Menin/PRMT5/hedgehog signaling: a potential target for the treatment of multiple endocrine neoplasia type 1 tumors. Epigenomics. 2013;5(5):469-71. doi: 10.2217/epi.13.47

Huang J, Gurung B, Wan B, et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature. 2012;482(7386):542-6. Published 2012 Feb 12. doi:10.1038/nature10806