Qianben Wang

Overview:

My laboratory is primarily interested in understanding the epigenetic mechanisms driving progression of hormone-dependent cancers. We focus on studying how transcription factor-centered, multi-layer transcription regulatory networks drive hormone-dependent cancers, which involve transcription factors (e.g. nuclear hormone receptors, FOXA1, and GATA2), transcription coactivators (e.g. Mediator and histone acetyltransferases), and epigenetic regulators (e.g. histone modifications, chromatin looping and nucleosome positioning).

Positions:

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

University of Maryland, Baltimore

Postdoctoral Fellow/Instructor in Molecular and Cellular Oncology, Dana Farber Cancer Institute

Harvard Medical School

Grants:

Systems Analysis of Epigenomic Architecture in Cancer Progression (Project 2: Fine-scale nucleosome repositioning of enhancers for hormone-independent genomic function)

Administered By
Pathology
Role
Principal Investigator
Start Date
End Date

Role of oncogenic phosphorylated MED1 in aggressive prostate cancer

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Novel genomic mechanism for ligand-dependent transcription by androgen receptor

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Novel Tumor Suppressive Role of Phosphodiesterases in Prostate Cancer

Administered By
Pathology
Awarded By
Ohio State University
Role
Principal Investigator
Start Date
End Date

Population/single-cell profiling of chromatin accessibility for hormone-dependent cancers

Administered By
Pathology
Awarded By
University of Texas Health Science Center at San Antonio
Role
Principal Investigator
Start Date
End Date

Publications:

Prostate Cancer Cell Phenotypes Remain Stable Following PDE5 Inhibition in the Clinically Relevant Range.

Widespread cGMP-specific phosphodiesterase 5 (PDE5) inhibitor use in male reproductive health and particularly in prostate cancer patients following surgery has generated interest in how these drugs affect the ability of residual tumor cells to proliferate, migrate, and form recurrent colonies. Prostate cancer cell lines were treated with PDE5 inhibitors at clinically relevant concentrations. Proliferation, colony formation, and migration phenotypes remained stable even when cells were co-treated with a stimulator of cGMP synthesis that facilitated cGMP accumulation upon PDE5 inhibition. Surprisingly, supraclinical concentrations of PDE5 inhibitor counteracted proliferation, colony formation, and migration of prostate cancer cell models. These findings provide tumor cell-autonomous evidence in support of the field's predominant view that PDE5 inhibitors are safe adjuvant agents to promote functional recovery of normal tissue after prostatectomy, but do not rule out potential cancer-promoting effects of PDE5 inhibitors in the more complex environment of the prostate.
Authors
Hankey, W; Sunkel, B; Yuan, F; He, H; Thomas-Ahner, JM; Chen, Z; Clinton, SK; Huang, J; Wang, Q
MLA Citation
Hankey, William, et al. “Prostate Cancer Cell Phenotypes Remain Stable Following PDE5 Inhibition in the Clinically Relevant Range.Transl Oncol, vol. 13, no. 9, Sept. 2020, p. 100797. Pubmed, doi:10.1016/j.tranon.2020.100797.
URI
https://scholars.duke.edu/individual/pub1442201
PMID
32454444
Source
pubmed
Published In
Translational Oncology
Volume
13
Published Date
Start Page
100797
DOI
10.1016/j.tranon.2020.100797

Shaping Chromatin States in Prostate Cancer by Pioneer Transcription Factors.

The androgen receptor (AR) is a critical therapeutic target in prostate cancer that responds to antagonists in primary disease, but inevitably becomes reactivated, signaling onset of the lethal castration-resistant prostate cancer (CRPC) stage. Epigenomic investigation of the chromatin environment and interacting partners required for AR transcriptional activity has uncovered three pioneer factors that open up chromatin and facilitate AR-driven transcriptional programs. FOXA1, HOXB13, and GATA2 are required for normal AR transcription in prostate epithelial development and for oncogenic AR transcription during prostate carcinogenesis. AR signaling is dependent upon these three pioneer factors both before and after the clinical transition from treatable androgen-dependent disease to untreatable CRPC. Agents targeting their respective DNA binding or downstream chromatin-remodeling events have shown promise in preclinical studies of CRPC. AR-independent functions of FOXA1, HOXB13, and GATA2 are emerging as well. While all three pioneer factors exert effects that promote carcinogenesis, some of their functions may inhibit certain stages of prostate cancer progression. In all, these pioneer factors represent some of the most promising potential therapeutic targets to emerge thus far from the study of the prostate cancer epigenome.
Authors
Hankey, W; Chen, Z; Wang, Q
MLA Citation
Hankey, William, et al. “Shaping Chromatin States in Prostate Cancer by Pioneer Transcription Factors.Cancer Res, vol. 80, no. 12, June 2020, pp. 2427–36. Pubmed, doi:10.1158/0008-5472.CAN-19-3447.
URI
https://scholars.duke.edu/individual/pub1432765
PMID
32094298
Source
pubmed
Published In
Cancer Res
Volume
80
Published Date
Start Page
2427
End Page
2436
DOI
10.1158/0008-5472.CAN-19-3447

Alternative polyadenylation of mRNA and its role in cancer

© 2019 Chongqing Medical University Alternative polyadenylation (APA) is a molecular process that generates diversity at the 3′ end of RNA polymerase II transcripts from over 60% of human genes. APA is derived from the existence of multiple polyadenylation signals (PAS) within the same transcript, and results in the differential inclusion of sequence information at the 3′ end. While APA can occur between two PASs allowing for generation of transcripts with distinct coding potential from a single gene, most APA occurs within the untranslated region (3′UTR) and changes the length and content of these non-coding sequences. APA within the 3′UTR can have tremendous impact on its regulatory potential of the mRNA through a variety of mechanisms, and indeed this layer of gene expression regulation has profound impact on processes vital to cell growth and development. Recent studies have particularly highlighted the importance of APA dysregulation in cancer onset and progression. Here, we review the current knowledge of APA and its impacts on mRNA stability, translation, localization and protein localization. We also discuss the implications of APA dysregulation in cancer research and therapy.
Authors
Yuan, F; Hankey, W; Wagner, EJ; Li, W; Wang, Q
MLA Citation
Yuan, F., et al. “Alternative polyadenylation of mRNA and its role in cancer.” Genes and Diseases, Jan. 2019. Scopus, doi:10.1016/j.gendis.2019.10.011.
URI
https://scholars.duke.edu/individual/pub1423340
Source
scopus
Published In
Genes and Diseases
Published Date
DOI
10.1016/j.gendis.2019.10.011

Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.

Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.
Authors
Lee, Y-Y; Mok, MT; Kang, W; Yang, W; Tang, W; Wu, F; Xu, L; Yan, M; Yu, Z; Lee, S-D; Tong, JHM; Cheung, Y-S; Lai, PBS; Yu, D-Y; Wang, Q; Wong, GLH; Chan, AM; Yip, KY; To, K-F; Cheng, ASL
MLA Citation
Lee, Ying-Ying, et al. “Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.Nucleic Acids Res, vol. 46, no. 17, Sept. 2018, pp. 8832–47. Pubmed, doi:10.1093/nar/gky589.
URI
https://scholars.duke.edu/individual/pub1331279
PMID
29992318
Source
pubmed
Published In
Nucleic Acids Res
Volume
46
Published Date
Start Page
8832
End Page
8847
DOI
10.1093/nar/gky589

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

Mutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.
Authors
Hankey, W; Chen, Z; Bergman, MJ; Fernandez, MO; Hancioglu, B; Lan, X; Jegga, AG; Zhang, J; Jin, VX; Aronow, BJ; Wang, Q; Groden, J
MLA Citation
Hankey, William, et al. “Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.Oncotarget, vol. 9, no. 58, July 2018, pp. 31214–30. Pubmed, doi:10.18632/oncotarget.25781.
URI
https://scholars.duke.edu/individual/pub1338242
PMID
30131849
Source
pubmed
Published In
Oncotarget
Volume
9
Published Date
Start Page
31214
End Page
31230
DOI
10.18632/oncotarget.25781