講師資料
Talks：
Circadian transcription factor BMAL1 and RNA-binding protein MEX3A co-regulate Lgr5+ stem cells and stress response in the intestine
Name：
黃雯華(Wendy W. Hwang-Verslues)
Position：
Assistant Research Fellow
Affiliation：
Genomics Research Center, Academia Sinica
Email：
Photo：
Research Interests：
Wendy Hwang-Verslues is using cell-based and mouse models to investigate the interplay between cancer and circadian rhythms/core clock genes. She aims to understand how disruption of circadian rhythm or dysregulation of core clock genes influences cancer initiation and progression. She wants to mechanistically link circadian regulation to cancer development to provide new strategies or targets for disease prevention and treatment.
Selected Publications：
1. Chang P.-H., Chen M.-C., Tsai Y.-P., Tan G.Y.T., Hsu P.-H., Jeng Y.-M., Tsai T.-F., Yang M.-H., Hwang-Verslues W.W.* [2021] Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer. Proceedings of National Academy of Sciences, U.S.A. 118 (3) e2014408118; https://doi.org/10.1073/pnas.2014408118
2. Yu, C.-W.*, Cheng, K.-C.*, Chen, L.-C., Lin, M.-X., Chang, Y.-C., Hwang-Verslues, W.W. [2018] Pro-inflammatory cytokines IL-6 and CCL2 suppress expression of circadian gene Period2 in mammary epithelial cells. (* equal contribution) Biochimica et Biophysica Acta Gene Regulatory Mechanisms 1861(11):1007-1017.
3. Chen L.-C., Hsieh Y.-L., Tan G.Y.T., Kuo T.-Y., Chou Y.-C.F, Hsu P.H. b, Hwang-Verslues W.W.* [2021] Differential Effects of SUMO1 and SUMO2 on Circadian Protein PER2 Stability and Function. Scientific Reports, 13;11(1):14431. doi: 10.1038/s41598-021-93933-y
4. Huang, S.-C., Wei, P.-C., Hwang-Verslues, W.W., Kuo, W.-H., Jeng, Y.-M., Hu, C.-M., Shew, J.-Y., Huang, C.-S., Chang, K.-J., Lee, E. Y.-H. P. and Lee W.-H [2017] TGF-β1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via up-regulation of IL-17RB. EMBO Molecular Medicine 9(12):1660-1680.
5. Cheung, S.K.C., Chuang, P.-K., Huang, H.-W., Hwang-Verslues, W.W., Cho C.H.-H., Yang, W.-B., Shen, C.-N., Hsiao, M., Hsu, T.-L., Chang, C.-F., Wong, C.-H. [2016] Stage-Specific Embryonic Antigen-3 (SSEA-3) and β3GalT5 are Cancer Specific and Significant Markers for Breast Cancer Stem Cells. Proceedings of National Academy of Sciences, U.S.A. 113(4):960-965.
6. Wu, H.-H*, Hwang-Verslues, W.W.*, Lee, W.-H., Huang, C.-K., Wei, P.-C., Chen, C.-L. , Shew, J.-Y., Lee, E. Y.-H. P., Jeng, Y.-M., Tien, Y.-W., Ma, C., Lee, W.-H. [2015] Targeting IL-17B/RB signaling with an anti-IL17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. (* equal contribution). Journal of Experimental Medicine 212(3):333-49.
7. Hwang-Verslues, W.W., Chang, P.-H., Jeng, Y.-M., Kou, W.-H., Chang, Y.-C., Chiang, P.-H., Hsieh, T.-H., Su, F.-Y., Lin, L.-C., Abbondante, S., Yang, C.-Y., Hsu, H.-M., Yu, J.-C., Chang, K.-J., Shew, J.-Y., Lee, E. Y.-H. P., Lee, W.-H. [2013] Loss of corepressor PER2 under hypoxia upregulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proceedings of National Academy of Sciences, U.S.A. 110(30):12331-12336.
Abstract：
Rapidly dividing intestinal stem cells (ISCs) are sensitive to chemotherapeutic agents, such as 5-fluorouracil (5-FU). Drug delivery at different times of day can change 5-FU toxicity; however, the underlying mechanism is unclear. We found that fast proliferating LGR5+ crypt base columnar (CBC) cells required for intestinal homeostasis are controlled by the circadian clock transcription factor BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A. BMAL1 directly activates Lgr5 transcription and MEX3A post-transcriptionally controls Lgr5 mRNA stability. Timing of 5-FU delivery when crypt cells had high BMAL1 and low Lgr5 protected ISCs from apoptosis. BMAL1 is critical for intestinal homeostasis and stress response as Bmal1 knockout in LGR5+ CBCs reduced MEX3A expression, decreased CBC numbers, and made ISCs more sensitive to 5-FU-induced apoptosis. Together, these findings demonstrate the central role of BMAL1 in ISC homeostasis and provide a biological explanation for chronotherapeutic chemoprotection.