YI-CHING WANG FAX: B.Sc. Ph.D.

Transcription

1 YI-CHING WANG POSITION/AFFILIATIONS CONTACT INFORMATION DISTINGUISHED PROFESSOR No.1, University Road, Department of Pharmacology & Tainan 70101, Taiwan, R. O. C. Institute of Basic Medical Sciences, TEL: ext.5502 College of Medicine, FAX: National Cheng Kung University EDUCATION INSTITUTION AND LOCATION DEGREE YEAR(S) FIELD OF STUDY Chinese Culture University Michigan State University B.Sc. Ph.D. 1983~ Horticulture Genetics Research Interests Dr. Wang studies the molecular mechanisms involved in lung tumorigenesis. Her group investigates the etiological association of alterations in tumor suppressor genes and oncogenes with lung tumorigenesis. The alteration analyses include the following aspects: gene mutation and polymorphism, gene amplification and loss, hypermethylation of promoter, chromatin structure alteration of gene locus, mrna alteration, and protein expression alteration. More recently, Dr. Wang has continued to do research on cancer genomics and epigenomics such as array comparative genomic hybridization, and genome-scanning approaches of DNA methylation and chromatin alteration profiles for identification of new genes critical to lung tumorigenesis. Several potential anti-cancer drugs also are developing in her laboratory. Positions and Employment 1993~1995 Post-doctoral fellow, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 1995~1999 Associate Professor, Institute of Toxicology, Chung Shan Medical Univ., Taichung, Taiwan 1999~2006 Professor, Department of Life Science, National Taiwan Normal Univ., Taipei, Taiwan 2006~present Distinguished Professor, Department of Pharmacology & Institute of Basic Medical Sciences & Institute of Clinical Medical Sciences, National Cheng Kung University, Tainan, Taiwan Awards 2004, 2010, 2014 Outstanding research award of Ministry of Science and Technology, Taiwan 2007 Distinguished alumnus of Chinese Culture University, Taiwan 2007~2013 Research award of Cheng-Shin Medical Foundation, Taiwan 2008 Outstanding research award, Pharmacology Society, Taiwan 2010 Outstanding research award, College of Medicine, National Cheng Kung University, Taiwan 2013 Outstanding research award of Basic Research, The Chinese Oncology Society, Taiwan

2 Academic Services 2000~present Editor board of the journal Lung Cancer 2010~present Editorial board of the journal American Journal of Translational Research 2011~present Editorial board of the journal Genomic Medicine, Biomarkers, and Health Sciences 2014 Guest editor of the journal Cell Bioscience on Thematic series: Transcriptional regulation and disease. 2000~present Reviewer for Journal of Clinical Oncology, Cancer Research, Clinical Cancer Research, Human Molecular Genetics, Oncogene, Oncotarget, Cancer, European Journal of Cancer, Journal of Pathology, Histololgy & Pathology, Molecular Cancer, Journal of Thoracic Oncology, Acta Pharmacologica Sinica, Gynecologic Oncology, Current Drug Targets, DNA and Cell Biology, BMC Cancer, International Journal of Medical Sciences, International Journal of Molecular Sciences, Targeted Proteins database, Respirology, BioMedical Sciences, and PLoS ONE. 2015~2018 President, The Taiwan Society for Biochemistry and Molecular Biology Selected publications (from a total of 87 peer-reviewed publications) 1. Tang YA, Chen CH, Sun S, Cheng CP, Tseng VS, Hsu HS, Su WC, Lai WW, Wang YC* Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer. Nucleic Acids Res. 43(3): Tsai CH, Cheng HC, Wang YS, Lin P, Jen J, Kuo IY, Chang YH, Liao PC, Chen RH, Yuan WC, Hsu HS, Yang MH, Hsu MT, Wu CY, Wang YC* Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumor metastasis. Nat Commun 5:4804 doi: /ncomms Lin RK, Wang YC* Dysregulated transcriptional and post-translational control of DNA methyltrasferases in cancer. Cell Biosci : 46 (invited review). 4. Cheng CP, Kuo IY, Alakus H, Frazer KA, Harismendy O, Wang YC*, Tseng VS* Network-based analysis identifies epigenetic biomarkers of esophageal squamous cell carcinoma progression. Bioinformatics 1;30(21): Yang YC, Tang YA, Shieh JM, Lin RK, Hsu HS, Wang YC* DNMT3B overexpression by deregulation of FOXO3a-mediated transcription repression and MDM2 overexpression in lung cancer. J. Thorac. Oncol. 9(9): Huang WJ, Tang YA, Chen MY, Wang YJ, Hu FH, Wang TW, Chao SW, Chiu HW, Yeh YL, Chang HY, Juan HF, Lin P, Wang YC* A histone deacetylase inhibitor YCW1 with antitumor and antimetastasis properties enhances cisplatin activity against non-small cell lung cancer in preclinical studies. Cancer Lett. 346:84-93 (featured article). 7. Kuo IY, Wu CC, Chang JM, Huang YL, Lin CH, Yan JJ, Sheu BS, Lu PJ, Chang WL, Lai WW, Wang YC* Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression. Int. J. Cancer 135: (cover article). 8. Chang HY, Huang HC, Huang TC, Yang PC*, Wang YC*, Juan HF* Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by activating the unfolded protein response. Cancer Res. 72: Lo FY, Chang JW, Chang IS, Chen YJ, Hsu HS, Huang SF, Tsai FY, Jiang SS, Kanteti R, Nandi S, Salgia R, Wang YC* The database of chromosome imbalance

3 regions and genes resided in lung cancer from Asian and Caucasian identified by array-comparative genomic hybridization. BMC Cancer 12(1): Tang YA, Lin RK, Tsai YT, Hsu HS, Yang YC, Chen CY, Wang YC* MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer. Clin. Cancer Res. 18: Lo FY, Tan YH, Cheng HC, Salgia R, Wang YC* An E3 ubiquitin ligase: c-cbl: a new therapeutic target of lung cancer. Cancer 117: (highlighted article). 12. Liu W, He L, Ramírez J, Krishnaswamy S, Kanteti R, Wang YC, Salgia R, Ratain MJ* Functional EGFR germline polymorphisms may confer risk for EGFR somatic mutations in non-small cell lung cancer, with a predominant effect on exon 19 microdeletions. Cancer Res. 71: Chen JY, Tang YA, Huang SM, Juan HF, Wu LW, Sun YC, Wang SC, Wu KW, Balraj G, Chang TT, Li WS, Cheng HC, Wang YC* A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer Angiogenesis and Metastasis Pathways. Cancer Res. 71: Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY, Lu YY, Tang YA, Yang YC, Yang PC, Wang YC* Dysregulation of p53/sp1 control leads to DNA methyltransferase 1 overexpression in lung cancer. Cancer Res. 70: Lin RK, Hsieh YS, Lin P, Hsu HS, Chen CY, Tang YA, Lee CF, Wang YC* The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J. Clin. Invest. 120: (cover article). 16. Tseng RC, Lee SH, Hsu HS, Chen BH, Tsai WC, Tzao C, Wang YC* SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res. 70: Tseng RC, Lee CC, Hsu HS, Tzao C, Wang YC* Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia 11: Chen CT*, Munot YS, Salunke SB, Wang YC*, Lin RK, Lin CC, Chen CC Triantennary dendritic galactoside-capped nanohybrid with ZnS/CdSe nanoparticle core as a hydrophilic, fluorescent, multivalent probe for metastatic lung cancer cells. Adv. Funct. Mater. 18: Chang JW, Huang TH, Wang YC* Emerging methods for analysis of the cancer methylome. Pharmacogenomics 9: (invited review) 20. Tseng RC, Lin RK, Wen CK, Tseng C, Hsu HS, Hsu WH, Wang YC* Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis. Oncogene 27: Tan YH, Lee KH, Lin T, Sun YC, Hsieh-Li HM, Juan HF, Wang YC* Cytotoxicity and proteomics analyses of OSU03013 in lung cancer. Clin. Cancer Res. 14: Hsu HS, Chen TP, Hung CH, Wen CK, Lin RK, Lee HC, Wang YC* Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma. Cancer 110: Lee MN, Tseng RC, Hsu HS, Chen JY, Tzao C, Ho WL, Wang YC* Epigenetic inactivation of the chromosomal stability control genes, BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin. Cancer Res. 13: Wang YC, Lin RK, Tan YH, Chen JT, Chen CY, Wang YC* Wild-type p53 overexpression and its correlation with MDM2 and p14arf alterations: an alternative pathway to non-small cell lung cancer. J. Clin. Oncol. 23: Tzao C, Tsai HY, Chen JT, Chen CY, Wang YC* 'CpG island hypermethylation and aberrant transcript splicing both contribute to the inactivation of the FHIT gene in

4 resected non-small cell lung cancer. Eur. J. Cancer 40: Wang YC*, Lu YP, Tseng RC, Lin RK, Chang JW, Chen JT, Shih CM, Chen CY Inactivation of hmlh1 and hmsh2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. J. Clin. Invest. 111: (highlighted article) 27. Chen JT, Chen YC, Wang YC, Tseng RC, Chen CY, Wang YC* Alterations of the p16 INK4a gene in resected non-small cell lung tumors and exfoliated cells within sputum. Int. J. Cancer 98: Chang JW, Chen YC, Chen CY, Chen JT, Chen SK, Wang YC* Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer. Clin. Cancer Res. 6: (highlighted article) 29. Wang YC*, Chen CY, Chen SK, Chang YY, Lin P p53 codon 72 polymorphism in Taiwanese lung cancer patients: association with lung cancer susceptibility and prognosis. Clin. Cancer Res. 5: Wang YC, Chen CY, Chen SK, Cherng SH, Ho WL, Lee H* High frequency of deletion mutations in p53 gene from squamous-cell lung cancer patients in Taiwan. Cancer Res. 58: Selected speeches in international meeting (from a total of 192 conference presentations) 1. 15th IUBMB-24th FAOBMB-TSBMB International Conference (2014/10/21~ 2014/10/25, Taipei, Taiwan) Rab37 small GTPase, a novel metastasis suppressor in lung cancer th Asian Conference on Transcription. (2014/2/19~2014/2/21, Melbourne, Australia) Deregulation of Oct4-centered transcriptional network in lung cancer. 3. Special Seminar at Department of Department of Molecular and Cellular Oncology, MD Anderson Cancer Center (2013/3/13, Houston, Texas, USA) Small GTPase Rab37 regulates tissue inhibitor of metalloproteinase 1 for exocytosis to inhibit cell migration and invasion and tumor metastasis. 4. The 12th Asian Conference on Transcription. (2012/6/6~2012/6/9, JeJu Island, Korea) ZNF322A overexpression leads to transcriptional deregulation of p53 and cyclin D1 in Asian and Caucasian Lung cancer. 5. Shanghai 3rd International Conference of Epigenetics in Development and Diseases (2012/4/19~2012/4/22, Shanghai, China) Deregulation of transcriptional and post-translational controls of DNA methyltransferases in lung cancer. 6. The 13th SCBA International Symposium (2011/6/14~2011/6/18, Guangzho, China) Is epigenetic target therapy a cure for cancer treatment? --drug design and cellular mechanism. 7. Italy-Taiwan meeting 2010, Italy (2010/10/4~2010/10/5, Italy) Comparative genomic and epigenomic studies to identify novel lung cancer-related genes in Asian and Caucasian populations. 8. 3rd World Cancer Congress 2010, Singapore (2010/6/22~2010/6/25, Singapore) Signal pathways involved in tobacco carcinogen-induced DNA methyltransferase 1 accumulation in lung cancer. 9. The 68th Annual Meeting of the Japanese Cancer Association (2009/10/1~2009/10/3, Yokohama, Japan) The role of p53 in mutator and methylator phenotypes in Taiwanese lung cancer th World Congress on Advances in Oncology and 11th International Symposium on Molecular Medicine (2008/10/9~2008/10/11, Crete, Greece) Alteration of HIC1-SIRT1-p53 circular regulation and distinct HIC1 inactivation mechanism in squamous cell carcinoma and adenocarcinoma lung cancer patients.

5 th World Conference on Lung Cancer. (2007/9/2~2007/9/6, Soul, Korea) Genomic and epigenomic instabilities in lung cancer: molecular mechanism and clinical implications. 12. America Association for Cancer Research (AACR) special conference in cancer research: Chromatin, chromosomes and cancer epigenetics. (2004/11/10~2004/11/14 USA) Overexpression of DNA methyltransferase genes in lung cancer and their association with 5 CpG hypermethylation, p53 mutation, and clinical implications. 13. Keystone Symposium on Epigenetics in Development and Disease (2002/2/21~ 2002/2/26 Tao City, USA) Inactivation of hmlh1 by genetic and epigenetic alterations, a novel mechanism causing non-small cell lung cancer. 14. The 2 nd international symposium on circulating nucleic acids in plasma and serum. (2002/11/14~2002/11/17 London, UK) Genetic, epigenetic, and proteomic biomarkers in lung cancer th International symposium on Predictive Oncology and Therapy: Impact of Biotechnology on cancer. (2000/10/28~2000/10/31 Geneva, Switzerland) Genome-wide analysis of loss of heterozygosity in non-small cell lung cancer. 16. American Association of Cancer Research (AACR) annual meeting (2000/4/1 ~ 2000/4/5 San Francisco, USA) Genetic instability of microsatellite sequences in lung cancer: correlation with p53 mutations and mismatch repair protein expression. Patents 1. Wang YC, Ching-Fa Yao / Catalyzed reaction for forming indole-based compounds and their preclinical animal and cell models for cancer treatment / Taiwan (I ) (2008~2028) 2. Wang YC, Wen-Shan Li, Hsieh-Fen Juan / Lithocholic acid derivatives as sialyltransferase inhibitors, their preparations, methods for identification of lead compounds, and treatment of cancer and metastasis. / Taiwan (I ) (2010~2026), USA (US ) (2015~2026) 3. Wang YC, I-Ying Kuo, I-Shou Chang / DNA methylation biomarkers for prognosis prediction of lung adenocarcinoma and a use thereof in clinical molecular prognosis of lung adenocarcinoma. Taiwan (I ) (2013~2031)

6 Tumorigenicity and Transcriptional Network of an Oncogenic Zinc Finger Protein ZNF322A in Lung Cancer Yi-Ching Wang, PhD Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan ZNF322A, which encodes a classical Cys2His2 zinc finger transcription factor, was previously revealed as a potential oncogene in lung cancer patients. However, the oncogenic role of ZNF322A and its underlying mechanism in lung tumorigenesis remain elusive. Here, we show high frequency of ZNF322A protein overexpression in Asian (71%, 87/123) and Caucasian (73%, 54/74) lung cancer patients. Multivariate Cox regression analysis indicated that ZNF322A was an independent risk factor for lung cancer poor outcome, corroborating the Kaplan-Meier results that patients with ZNF322A protein overexpression had significantly poorer overall survival than other patients. Overexpression of ZNF322A promoted cell proliferation and soft agar growth by prolonged cell cycle in S phase in multiple lung cell lines, including the immortalized lung cell BEAS-2B. In addition, ZNF322A overexpression enhanced cell migration and invasion. In contrast, knockdown of ZNF322A diminished cell growth, invasion and metastasis abilities in vitro and in vivo. To characterize the transcriptional mechanism of ZNF322A in lung cancer, we first revealed consensus DNA binding motifs of ZNF322A using CASTing assay and ChIP-seq analysis. We then identified putative transcriptional targets of ZNF322A by integrating ChIP-seq and RNA-seq datasets. Many of the ZNF322A transcriptional target genes were involved in cancer-related processes, such as transcription, cell cycle regulation, and migration. For example, we found that ZNF322A formed complex with c-jun and cooperatively activated alpha-adducin and cyclin D1 but repressed p53 gene transcription by recruiting differential chromatin modifiers, such as histone deacetylase 3, in an AP-1 element dependent manner using luciferase promoter activity assay combined with site-directed mutagenesis and sequential chromatin immunoprecipitation-pcr assay. Our results provide first evidence that overexpression of ZNF322A contribute to lung tumorigenesis and poor prognosis. The unbiased genomic analyses reveal de novo ZNF322A motifs and downstream target genes in lung cancer.