Yuesheng Zhang, M.D., Ph.D.


Yuesheng Zhang, M.D., Ph.D.Harrigan, Haw, and Luck Families Chair in Cancer Research, Massey Comprehensive Cancer Center

Department: Pharmacology and Toxicology

Phone: 804-628-8679

Email: Yuesheng.Zhang@vcuhealth.org

Massey Comprehensive Cancer Center
401 College Street
Richmond, VA 23298
Office: Goodwin Research Laboratory, Room 329


  • M.D., 1984, Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China.
  • M.S., 1988, Pathophysiology, Zhejiang University, College of Medicine, Hangzhou, China.
  • Ph.D., 1996, Department of Pharmacology and Molecular Sciences, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.

Research Interests

  • Therapeutic targets and drug development for cancer prevention and treatment

I have had a long-standing interest in cancer chemoprevention. In the past several years, however, my main research focus has been on the novel functions of peptidase D (PEPD), stemming from discoveries made in my cancer chemoprevention research. PEPD is commonly known as a dipeptidase important for collagen metabolism, as it recycles proline and hydroxyproline which are very abundant in collagen. PEPD hydrolyzes dipeptides with C-terminal proline or hydroxyproline (e.g., glycine-proline). Unexpectedly, we discovered that PEPD does three important things that are independent of its enzymatic activity. We first found that exogenously delivered recombinant human PEPD and enzymatically inactive PEPD-G278D bind to the extracellular domains of epidermal growth factor receptor (EGFR) and its family member HER2 and induce their internalization and degradation. The enzymatic activity of PEPD is not required for this function. EGFR and HER2 are oncogenic receptor tyrosine kinases and major therapeutic targets in many types of human cancer. PEPD and PEPD-G278D are potent inhibitors of EGFR and HER2 and inhibits the growth of cancer cells over-expressing EGFR and/or HER2 in vitro and in vivo. We later focused on PEPD-G278D, because our results show that it is a more promising antitumor agent than PEPD. Our recent study shows that PEPD-G278D is highly effective against drug-resistant HER2-positive breast cancer. We are continuing this line of research and hope to initiate clinical evaluation of this agent in the near future.

While intracellularly expressed PEPD has no effect on EGFR and HER2, we found that intracellular PEPD binds to and regulates p53 tumor suppressor and mutant p53. PEPD regulation of p53 is also independent of its enzymatic activity. p53 tumor suppressor is one of the most critical determinants of the fate of both normal cells and cancer cells. It has been called “the cellular gatekeeper” or “the guardian of the genome”. Not surprisingly, p53 activity must be tightly regulated. The existing model of p53 activation includes three key steps: 1) p53 stabilization due to its phosphorylation and other modifications in response to stress, 2) transcriptional modulation of target genes by p53 via sequence-specific DNA binding, and 3) transcription-independent activity such as mitochondrial translocation. In this model, the most important event is the uncoupling of p53 from MDM2, an E3 ubiquitin ligase which directs the ubiquitination and proteasomal degradation of p53. However, we have found that about half of cellular p53 binds via its proline-rich domain to PEPD, and that disrupting the p53-PEPD complex activates p53, which causes cell death and tumor regression. Our results indicate that the p53-PEPD complex is physiologically important, as it stores p53 for rapid response to stress. Moreover, PEPD also binds to p53 mutants. TP53 encodes p53 and is the most frequently mutated gene in cancer. Most TP53 mutations in cancer are missense mutations, resulting in a single amino acid change in each mutant. It is well known that p53 mutation may nullify its tumor suppressor functions or endow oncogenic functions (dominant negative or gain of function). However, the proline-rich domain in p53 is rarely mutated. Most surprisingly, our study shows that disrupting the mutant p53-PEPD complex reactivates the mutant p53. Thus, our studies have uncovered a cellular mechanism that restores the tumor suppressor functions of p53 mutants and suggest that intracellular PEPD is a promising cancer therapeutic target for activation of p53 and reactivation of p53 mutants. We are continuing this line of research as well.


Selected publications

  1. Yang L, Bhattacharya A, Li Y, Sexton S, Ling X, Li F, Zhang Y. Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer. Journal of Experimental & Clinical Cancer Research, 41, 184, 2022.
  2. Yang L, Li Y, Bhattacharya A, Zhang Y. Loss of peptidase D binding restores the tumor suppressor functions of oncogenic p53 mutants. Communications Biology, 4, 1373, 2021.
  3. Yang L, Li Y, Bhattacharya A, Zhang Y. A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer. Science Translational Medicine, 11, eaav1620, 2019.
  4. Li Y, Chen D, Paonessa JD, Meinl W, Bhattacharya A, Glatt H, Vouros P, Zhang Y. Strong impact of sulfotransferases on DNA adduct formation by 4-aminobiphenyl in bladder and liver in mice. Cancer Medicine, 7, 5604-5610, 2018.
  5. Yang L, Li Y, Bhattacharya A, Zhang Y. PEPD is a pivotal regulator of p53 tumor suppressor. Nature Communications, 8, 2052, 2017.
  6. Yang L, Li Y, Bhattacharya A, Zhang Y. Inhibition of ERBB2-overexpressing tumors by recombinant human prolidase and its enzymatically inactive mutant. EBioMedicine, 2,396- 405, 2015.
  7. Yang L, Li Y, Zhang Y. Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth. Cell Death & Disease, 5, e1211, 2014.
  8. Zucker S, Fink E, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner P, Wawrzyniak JA, Foley C, Leonova KI, Grimm M, Moparthy K, Ionov Y, Wang J, Liu S, Sexton S, Kandel ES, Bakin A, Zhang Y, Kaminski N, Segal B, Nikiforov M. Nrf2 amplifies oxidative stress via induction of Klf9. Molecular Cell, 53, 916-928, 2014.
  9. Yang L, Li Y, Ding Y, Choi KS, Kazim AL, Zhang Y. Prolidase directly binds and activates epidermal growth factor receptor and stimulates downstream signaling. Journal of Biological Chemistry, 288, 2365-2375, 2013.
  10. Li Y, Paonessa JD, Zhang Y. Mechanism of chemical activation of Nrf2. PLoS ONE, 7, e35122, 2012.
  11. Geng F, Tang L, Li Y, Yang L, Choi KS, Kazim AL, Zhang Y. Allyl isothiocyanate arrests cancer cells in mitosis, and mitotic arrest in turn leads to apoptosis via Bcl-2 phosphorylation. Journal of Biological Chemistry, 286, 32259-32267, 2011.
  12. Paonessa JD, Ding Y, Randall KL, Munday R, Argoti D, Vouros P, Zhang Y. Identification of an unintended consequence of Nrf2-directed cytoprotection against a key tobaccocarcinogen plus a counteracting chemopreventive intervention. Cancer Research, 71, 3904-3911, 2011.
  13. Ding Y, Paonessa JD, Randall KL, Argoti D, Chen L, Vouros P, Zhang Y. Sulforaphane inhibits 4-aminobiphenyl-induced DNA damage in bladder cells and tissues. Carcinogenesis, 31, 1999-2003, 2010.
  14. Bhattacharya A, Tang L, Li Y, Geng F, Paonessa JD, Chen SC, Wong MKK, Zhang Y. Inhibition of bladder cancer development by allyl isothiocyanate. Carcinogenesis, 31, 281- 286, 2010.
  15. Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Ambrosone CB, McCann SE. Consumption of raw cruciferous vegetables is inversely associated with bladder cancer risk. Cancer Epidemiology, Biomarkers & Prevention, 17, 938-944, 2008.
  16. Munday R, Mhawech-Fauceglia P, Munday CM, Paonessa JD, Tang L, Munday JS, Lister C, Wilson P, Fahey JW, Davis W, Zhang Y. Inhibition of urinary bladder carcinogenesis by broccoli sprouts. Cancer Research, 68, 1593-1600, 2008.
  17. Zhang Y, Tang L. Discovery and development of sulforaphane as a cancer chemopreventive phytochemical. Acta Pharmacologica Sinica, 28, 1343-1354, 2007.
  18. Tang L, Zhang Y, Jobson HE, Li J, Stephenson KK, Wade KL, Fahey JW. Potent activation of mitochondria-mediated apoptosis and arrest in S and M phases of cancer cells by a broccoli sprout extract. Molecular Cancer Therapeutics, 5, 935-944, 2006.
  19. Tang L, Zhang Y. Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells. Molecular Cancer Therapeutics, 4, 1250-1259, 2005.
  20. Zhang Y. Cancer-Preventive Isothiocyanates: Measurement of human exposure and mechanisms of action. Mutation Research, 555, 173-190, 2004.
  21. Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates possess potent anti-proliferative activity in vitro. Molecular Cancer Therapeutics, 2, 1045-1052, 2003.
  22. Zhang Y, Talalay P. Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic phase 2 enzymes. Cancer Research, 58, 4632-4639, 1998.
  23. Fahey JW, Zhang Y, Talalay P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proceedings of the National Academy of Sciences of the United States of America, 94, 10367-10372, 1997.
  24. Zhang Y, Wade KL, Prestera T, Talalay P. Quantitative determination of isothiocyanates, dithiocarbamates, carbon disulfide, and related thio carbonyl compounds by cyclocondensation with 1,2-benzenethiol. Analytical Biochemistry, 239, 160-167, 1996.
  25. Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proceedings of the National Academy of Sciences of the United States of America, 91, 3147-3150, 1994.
  26. Zhang Y, Talalay P, Cho C-G, Posner GH. A Major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure, Proceedings of the National Academy of Sciences of the United States of America, 89, 2399-2403, 1992.
  27. Zhang Y, Chen X, Yu Y. Antimutagenic effects of garlic (Allium Sativum L.) on 4-NQO- induced mutagenesis in escherichia coli WP2. Mutation Research, 227, 215-219, 1989.

See all publications at https://www.ncbi.nlm.nih.gov/sites/myncbi/yuesheng.zhang.1/bibliography/40831490/public/?sort=date&direction=ascending

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