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Sept. 28th Seminar - Mien-Chie Hun

 Crosstalk signaling pathways in cancer cells

Mien-Chie Hung, PhD

Vice President for Basic Research

Professor and Chairman, Department of Molecular and Cellular Oncology

Director of Center for Biological Pathways

Director of Breast Cancer Basic Research Program

Distinguished Teaching Professor

Ruth Legett Jones Distinguished Chair

The University of Texas, MD Anderson Cancer Center


1996-present: Chairman and Endowed Professor, Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center

2003-present: Vice President for Basic Research, University of Texas MD Anderson Cancer Center,

Dr. Mien-Chie Hung is a distinguished cancer biologist. During his scientific career, he has published over 430 peer-reviewed publications with lifetime h-index of 97 and 93 publications are cited over 100 times (Web of Science). He has trained 52 Ph.D. students, and directly supervised 144 postdoctoral trainees, 11 clinical fellows and 13 physician scientists. Most of his trainees hold academic positions in US and other countries.


Previously, we unraveled a non-canonical pathway of Hedgehog (Hh) through mTOR in addition to established, or canonical, pathway for activating Gli1 that both pathways converge to Gli1 (Cancer Cell 21:374, 2012). Hedgehog inhibitor GDC-0449 (Erivedge®) was approved by the FDA in February 2012 for treatment of metastatic basal cell carcinoma, but in other cancers, such as ovarian and pancreas are resistant to GDC-0449. Our finding serve as a guidance for clinical trials of the combination for esophageal and other cancers that could be directed by the antibody for phosphorylated Gli1 and the presence of plain Gli1, which would indicate a need to use both drugs. 

Gli1 has been shown to be functionally involved in pancreatic ductal adenocarcinoma (PDAC), and is activated in PDAC cells through non-canonical Hedgehog (Hh) pathway and in tumor-associated stoma cells through canonical Hh pathway. Recently, we identified Gli1 as a substrate of protein arginine N-methyltransferase 1 (PRMT1) in PDAC. Interruption of Gli1 methylation attenuates Gli1 oncogenic effects as well as sensitizes PDAC cells to gemcitabine. Interestingly, the regulation of Gli1 by PRMT1 is independent of canonical Hh pathway and the previously identified non-canonical Hh pathway through mTOR/S6K1, suggesting the new regulation mechanisms of Gli1 in PDAC. Taken together, our work supported a novel post-translational modification of Gli1 by PRMT1 (Mol Cell, under revision).

Furthermore, we identified that EGFR is another novel substrate of PRMT1.  Methylation-defective EGFR mutant reduced tumor growth in mouse orthotopic xenograft model. Importantly, increased EGFR methylation sustains its signaling activation and cell proliferation in the presence of therapeutic EGFR monoclonal antibody, cetuximab. EGFR methylation level also correlates with higher recurrence rate after cetuximab treatment and poorer overall survival in colorectal cancer patients. These data suggest that PRMT1-mediated EGFR methylation plays important role in regulating EGFR functionality and resistance to cetuximab treatment (JCI, in press). 

In this talk, I will also briefly summarize recent advances in role and function of EGFR in including its role in regulating mRNA maturation (Nature 497:383, 2013), DNA replication licensing (Cancer Cell 23:796, 2013), and effect of nuclear EGFR on DNA repair (Dev Cell 30:224, 2014; Cell Res 25:225, 2015; Nature Comm 6:7874, 2015). 

Time: September 28th.2015, 14:00

Venue: New Biology Building, Room 143

Host: Prof. Xin Lin




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