Wei Xu, PhD
Position title: Marian A. Messerschmidt Professor in Cancer Research, Department of Oncology
1111 Highland Ave
My laboratory is focused on the transcriptional regulation of estrogen receptor (ER) signaling pathways by nuclear receptor co-factors. We identified a natural plant product that significantly decreased ERa but increased ERb stability. Via distinct mechanism from the existing agents for endocrine therapy, this compound also significantly promoted degradation of mutant ERa that is found in ~25% of patients with metastatic ERa-positive breast cancers. Biological functions of these estrogenic compounds have been investigated in cell-based and breast cancer mouse models. The bioactive derivatives may be developed as novel agents for treating metastatic, endocrine-resistant breast cancers caused by ERa mutations. Furthermore, we investigated the crosstalk between ERa pathways and other growth factors (e.g., HER2) and kinase networks, as these mechanisms account for the intrinsic or acquired endocrine resistance.
The second focus of our lab is to elucidate epigenetic regulation of cell signaling and transcription by CARM1-mediated methylation of histone and non-histone substrates, and to reveal how arginine methylation contributes to diverse biological functions. Global profiling of CARM1 substrates identified over 130 bona fide CARM1 protein substrates. We have shown that methylation of discreate cancer-relevant substrates regulates distinct hallmarks of cancer. The study of MED12 methylation by CARM1 in regulating chemosensitivity and BAF155 methylation in promoting metastasis are funded by two NIH R01. BAF155 methylation drives cancer metastasis, providing the foundation for employing CARM1 inhibitors in cancer therapy. Overall, our systematic work elucidates mechanistic foundations of cancer dependencies on aberrant epigenetic programs and exploits this vulnerability to develop novel therapies.
Honors & Awards
- Shaw Scientist Award, 2008
- DOD ERA of HOPE Scholar, 2010
- Society of Toxicology Achievement Award, 2013
- Villas Distinguished Achievement Professor, University of Wisconsin, 2014
- Romnes Faculty Fellowship, University of Wisconsin, 2016
- Marian A. Messerschmidt Professorship, 2016
- AACR-Bayer Innovation and Discovery Grant Awardee, 2019
- Kellett Mid-Career Award, University of Wisconsin-Madison, 2019
- Liu F., Ma, M., Ma, F., Liu, P., Jia, C., Wang, Y., Zhang, S., Ong, I., Keles, S., Li, L., Xu, W. (2021) PKM2-TMEM33 axis controls SCAP stability and lipid homeostasis in cancer. EMBO J. Sept. 6; e108065. PMID: 34487377
- Liu F.B., Ma F., Wang Y., Hao L., Zeng, H., Jia, C., Liu, P., Ong, I., Li, B., Chen G., Jiang, J., Wang, Y., Gong, S., Li, L., and Xu, W. (2017) PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis, Nature Cell Biology, 19: 1358-1370.
- Shishkova E., Zeng, H., Liu, F.B., Coon, J., Xu, W. (2017) Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition, Nature Comm., 8: 15571
- Zhao, Z., Wang, L., James, T., Jung, Y., Kim, I., Tan, R., Hoffmann, M. and Xu, W. (2015) Reciprocal regulation of ERα and ERβ stability and activity by Diptoindonesin G. Chemistry & Biology, 22: 1-14.
- Zeng, H. and Xu, W. (2015) Ctr9, a key subunit of PAFc, affects global estrogen signalling and drives ERα -positive breast tumorigenesis. Genes & Development, 29: 2153-67.
- Wang, L., Zeng, H., Wang, Q., Zhao, Z., Boyer T. G., Bian, X., and Xu, W. (2015) MED12 methylation by CARM1 sensitizes human breast cancer cells to chemotherapy drugs. Science Advances, 1: e1500463.
- Wang, L., Zhao, Z., Meyer, M. B., Saha, S., Yu, M., Guo, A., Wisinski, K. B., Huang, W., Cai, W., Pike, J. W., Yuan, M., Ahlquist, P., Xu, W. (2014) CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell, 25: 1-16.