Hwang-Verslues, Wendy W. 黃雯華

WendyH V6x7助研究員


wendyhvgateEmail
02-27871246
Lab phone: 02-27898804

 

 

 

EDUCATION AND POSITIONS HELD:

  • Ph.D., Environmental Toxicology, University of California-Riverside, June 2007
  • Master of Environmental Management, Environmental Toxicology, Chemistry and Risk Assessment, Duke University, May 2002
  • Postdoctoral Fellow, Genomics Research Center, Academia Sinica, Jan 2008- Dec 2014
  • Research Scientist, Department of Biology, Washington University in St. Louis, Sep 2014- May 2015
  • Assistant Professor, Genomics Research Center, Academia Sinica, Dec 2015-present

HONORS:

GRANTS AWARDED

National Taiwan University and Academia Sinica Innovative Joint Program [AS-NTU-110-09]
Amount: NT 700,000
Period: 1/2021‐12/2021
Role: Project Director Project
Title: Bi-directional regulation between epithelial-mesenchymal transition (EMT) and circadian gene Period2 (PER2) in epithelial ovarian cancer (OC)

VGH, TSGH, AS Joint Research Program [AS-VTA-110-12]
Amount: NT 500,000
Period: 1/2021‐12/2021
Role: Project Director
Project Title: Determine whether the interplay between inflammasome and cancer stem cell characteristics contributes to endometriosis associated epithelial ovarian cancer initiation and progression

Ministry of Science and Technology, Taiwan [MOST-108-2311-B-001-005-MY3]
Amount: NT 3,540,000
Period: 8/2019‐7/2022
Role: Project Director
Project Title: Mechanisms and significance of circadian core protein PER2 SUMOylation

Ministry of Science and Technology, Taiwan [MOST-105-2628-B-001-008-MY3]
Amount: NT 3,450,000
Period: 8/2016‐7/2019
Role: Project Director
Project Title: Links between circadian gene and hypoxia in breast cancer progression

OTHERS

  • Taiwan National Science Council 2013 Postdoctoral Fellow Academic Publication Award
  • The 72nd Annual Meeting of the Japanese Cancer Association Travel Grant Award Oct 2013
  • The 1st GRC Best Performance-and-Service Award, Genomics Research Center, Academia Sinica, Feb 2012
  • The 70th Annual Meeting of the Japanese Cancer Association Travel Grant Award Oct 2011
  • Academia Sinica Postdoctoral Research Fellowship Jan 2010- Dec 2011
  • Academia Sinica Distinguished Postdoctoral Scholar Fellowship Jan 2008- Dec 2009
  • Sigma Xi Grants-in-Aid of Research Award, Jan 2007
  • Fukuto Award, University of California-Riverside June 2006

RESEARCH INTERESTS:

Long term goals of the Hwang-Verslues laboratory are to decipher the links among circadian rhythm, core clock gene functions and stem cell (SC) fate/characteristics in tissue development and disease progression.

Program 1 is to use mice and cell cultures as models to investigate whether circadian rhythms or core clock genes contribute to intestinal SC (ISC) fate determination, and how the circadian clocks in the brain and the intestine coordinate with each other to regulate ISC fate. We also aim to understand how heterogeneous cell types in the intestine synchronize their circadian rhythms to generate a SC niche and how the circadian-SC relationship influences disease development, such as chronic inflammation and cancer. By mechanistically linking circadian regulation to SC fate and function, we will not only gain fundamental knowledge in chronobiology but also provide new strategies or targets for disease prevention and treatment.

Hwang Verslues Lab F1
Diagram depicts our main research program to investigate the relationship among the master clock, intestinal peripheral clock, the intestinal (cancer) stem cell self- renewal and differentiation.

 

Program 2 focuses on regulation of Period 2 (PER2), a core circadian regulatory factor, in both normal and cancerous condition. In peripheral tissues, the circadian genes have tissue specific functions and play important roles in tissue specific responses to the circadian environment (1-3). We previously found that PER2 acted as a tumor suppressor in normal breast cells (4). Loss of the PER2 allowed activation of EMT gene expression, enhancement of invasion and elevation of breast cancer stem cell (CSC) prevalence (4). This new role of PER2 may be particularly relevant in understanding the association of disrupted circadian rhythm due to both external or intrinsic factors and increased cancer incidence that has been observed in epidemiological studies (5-7). Despite the fact that PER2 exhibits tumor suppressor function and is downregulated in breast cancer cells, it is not clear how PER2 suppression occurs in pre-cancerous mammary epithelial cells. We found that IL-6 and CCL2 from the inflammatory microenvironment suppressed PER2 expression in phenotypic normal breast epithelial cells to promote cancer stemness and tumorigenic potential (8). Reduced PER2 expression was observed over a time scale of hours to weeks following IL-6/CCL2 stimulation. This suggested that PER2 suppression occurs in the early stage of interaction between an inflammatory microenvironment and normal breast epithelial cells. These data show that PER2 repression contributes to breast tumorigenesis and illustrate a new mechanism by which mammary cells interact with a cancerous microenvironment.

Hwang Verslues Lab F2

Diagram of the proposed mechanism by which pro-inflammatory cytokines
from the inflammatory microenvironment suppress PER2 gene expression
in breast epithelial cells.

PER2 is important for timely inhibition of circadian gene expression and reactivation of the transcription-translation feedback loop (TTFL) that drives circadian rhythms. A phosphoswitch between two competing PER2 phosphorylation (S662 versus S480) sites is known to control PER2 stability, localization and transcriptional repression activity. However, the mechanisms controlling this switch (ie: which PER2 site gets phosphorylated by CK1) have remained unknown. We show for the first time the importance of SUMOylation in controlling activity of the core circadian clock protein PER2. This SUMOylation may work upstream of and controls the critical PER2 phosphoswitch. The effect of PER2 SUMOylation during tumorigenesis is currently under investigation (Chen LC et al. bioRxiv doi: https://doi.org/10.1101/789222)

Program 3 is to identify new factors driving cancer metastasis. Metastasis is the major cause of cancer death. Circulating tumor cells (CTCs) is particularly associated with colonization of distant organs and poor prognosis. We found that expression of cell adhesion molecule Desmoglein2 (DSG2) is correlated with poor prognosis and recurrence risk in breast cancer patients. High DSG2 expression promoted tumor growth, increased clustered CTCs and facilitated distant organ colonization. When hypoxia occurred, HIF1α directly bound and recruited polycomb repressive complex 2 components to suppress the DSG2 promoter activity. Downregulation of DSG2 led to elevated EMT and enhanced invasion ability of cancer cells, thus allowing cells to detach from the primary tumor and undergo intravasation. Once hypoxic stress was released in the vascular system and lung tissues, DSG2 was de-repressed allowing CTCs to colonize in distant organs. Together, our results demonstrated the role of DSG2 expression in breast cancer metastasis and revealed a new molecular mechanism by which hypoxia drives metastasis. (Chang P.H. et al., Proceedings of National Academy of Sciences, U.S.A., in press; bioRxiv doi: https://doi.org/10.1101/790519)

 Hwang Verslues Lab F3

Dynamic changes of DSG2 expression contribute to breast tumorigenesis and metastasis.

 

 Hwang Verslues Lab 2019
Hwang-Verslues Lab 2019

 

SELECTED PUBLICATIONS:

  • Ling-Chih Chen, Yung-Lin Hsieh, Grace Y.T. Tan, Tai-Yun Kuo, Yu-Chi Chou, Pang-Hung Hsu, Wendy W Hwang-Verslues*, 2021, “Differential Effects of SUMO1 and SUMO2 on Circadian Protein PER2 Stability and Function”, SCIENTIFIC REPORTS, 11, 14431. (SCIE) (IF:  ;  )
  • Po-Hao Chang, Min-Che Chen, Ya-Ping Tsai, Grace Y.T. Tan, Pang-Hung Hsu, Yung-Ming Jeng, Yi-Fang Tsai, Muh-Hwa Yang, Wendy W. Hwang-Verslues*, 2021, “Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer”, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118(3), e2014408118. (SCIE)
  • Fararjeh, A., Tu, S.H., Chen, L.C., Cheng, T.C., Liu, Y.R., Chang, H.L., Chang, H.W., Huang, C.C., Wang, H.C.R., Hwang-Verslues, W.W., Wu, C.H., Ho, Y.S.*, 2019, “Long-term exposure to extremely low-dose of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce non-malignant breast epithelial cell transformation through activation of the a9-nicotinic acetylcholine receptor-mediated signaling pathway”, ENVIRONMENTAL TOXICOLOGY, 34(1), 73-82. (SCIE)
  • 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”, BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, 1861(11), 1007-1017. (SCIE)
  • Fattah Fararjeh-Salah Abdul, Tu Shih-Hsin, Chen Li-Ching, Liu Yun-Ru, Lin Yen-Kuang, Chang Hang-Lung, Chang Hui-Wen, Wu Chih-Hsiung, Verslues Wendy-Hwang, Ho Yuan-Soon, 2018, “The Impact of the effectiveness of GATA3 as a prognostic factor in breast cancer”, Human Pathology, 80, 219-230. (SCIE)
  • Wu YW, Hsu KC, Lee HY, Huang TC, Lin TE, Chen YL, Sung TY, Liou JP, Hwang-Verslues WW, Pan SL, Huang-Fu WC,, 2018, “A novel dual HDAC6 and tubulin inhibitor, MPT0B451, displays anti-tumor ability in human cancer cells in vitro and in vivo”, FRONTIERS IN PHARMACOLOGY, 9, 205. (SCIE)
  • Huang S.-C., Wei P.-C., Hwang-Verslues W.W., Kuo W.-H., Jeng Y.-M., Hu C.-H., Shew J.-Y., Huang C.-S., Chang K.-J., Lee E. Y.-H. P., 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. (SCIE)
  • 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 the National Academy of Sciences of the United States of America, 113(4), 960-965. (SCIE)
  • 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”, JOURNAL OF EXPERIMENTAL MEDICINE, 212(3), 333-349. (SCIE)
  • Hwang-Verslues WW, Chang PH, Jeng YM, Kuo WH, Chiang PH, Chang YC, Hsieh TH, Su FY, Lin LC, Abbondante S, Yang CY, Hsu HM, Yu JC, Chang KJ, Shew JY, Lee EY, Lee WH, 2013, “Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy.”, Proceedings of the National Academy of Sciences of the United States of America, 110(30), 12331-6. (SCIE)
  • Chang, P.-H., Hwang-Verslues, W.W., Chang, Y.-C., Chen, C.-C., Hsiao, M., Jeng, Y.-M., Chang, K.-J., Lee, E. Y.-H. P., Shew, J.-Y., Lee, W.-H., 2012, “Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/β-catenin pathway”, CANCER RESEARCH, 72(18), 4652-4661. (SCIE)
  • Hwang-Verslues, W.W.*, Lee, W.-H., Lee, E.Y.-H.P., 2012, “Biomarkers to target heterogeneous breast cancer stem cells (invited review)”, Journal of Molecular Biomarkers & Diagnosis, S8, 006.
  • Bolotin, E., Chellappa, K., Hwang-Verslues, W.W., Schnabl, J.M., Yang, C., Sladek, F.M., 2011, “Nuclear receptor HNF4a binding sequences are widespread in Alu repeats”, BMC GENOMICS, 12, 560. (SCIE)
  • Hwang-Verslues, W.W., Chang P.-H., Wei P.-C., Yang C.-Y., Huang C.-K., Kuo W.-H., Shew J.-Y., Chang K.-J., Lee E.-Y., Lee W.-H., 2011, “miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1”, ONCOGENE, 30(21), 2463-2474. (SCIE)
  • Hwang-Verslues, W.W., Sladek, F.M., 2010, “HNF4a-role in drug metabolism and potential drug target? (review)”, CURRENT OPINION IN PHARMACOLOGY, 10(6), 698-705. (SCIE)
  • Bolotin E., Liao H., Ta T.C., Yang C., Hwang-Verslues W.W., Evans J.R., Jiang T., Sladek F.M., 2010, “Integrated approach for identification of HNF4α target genes using protein binding microarrays”, HEPATOLOGY, 51(2), 642-653. (SCIE)
  • Hwang-Verslues, W.W., Kuo W.-H., Chang P.-H. Pan C.-C., Wang H.-H., Tsai S.-T., Jeng Y.-M., Shew J.-Y., Kung J.T, Chen C.-H., Lee E. Y.-H. P., Chang K.-J., Lee W.-H., 2009, “Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers”, PLoS One, 4(12), e8377. (SCIE)
  • Hwang-Verslues, W.W., Chang, K.J., Lee, E.Y-H.P., Lee, W.-H., 2008, “Breast cancer stem cells and tumor suppressor genes”, Journal of Formosan Medical Association, 107(10), 751-766.
  • Hwang-Verslues, W.W., Sladek, F.M., 2008, “Nuclear receptor HNF4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter”, MOLECULAR ENDOCRINOLOGY, 22(1), 78-90.
  • Maeda, Y.*, Hwang-Verslues, W.W.*, Wei, G., Fukazawa, T., Durbin, M.L., Owen, L. B., Liu, X. and Sladek, F.M., 2006, “Tumor suppressor p53 down regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4a) gene”, BIOCHEMICAL JOURNAL, 400(2), 303-313. (SCIE)