Molecular Oncology & Biomarkers


Research projects in the Yan Laboratory are aimed at elucidating and therapeutically targeting transcriptional regulatory networks in cancer. A variety of molecular biology approaches, genomics/proteomics techniques, and genetically engineered mouse models are used to dissect protein-protein interaction networks and signaling pathways engaging in the cellular stress response and oncogenic transformation. Cutting-edge genome-editing tools are also applied to develop high-throughput platforms for searching for novel anti-cancer agents.

Regulation of the p53 tumor suppressor pathway by ATF3.

Based on our early finding that the common stress-responsive transcription factor ATF3 is a major p53 regulator by blocking its ubiquitination and degradation, we continue to dissect the mechanisms by which ATF3 regulates p53 in response to DNA damage and metabolic stresses. We found that ATF3 itself can be ubiquitinated and degraded by the p53 target MDM2, and thus appears to be involved in a negative feedback loop required for fine- tuning p53 activity in the DNA damage response. We further demonstrated that ATF3 interacts with a histone acetyltransferase (Tip60) upstream of the p53 pathway, thereby activating p53 through promoting the Tip60 enzymatic activity and its stabilization mediated by the deubiquitinase USP7. In addition, we showed that ATF3 can interact with mutant p53 proteins and consequently suppresses cancer cell chemoresistance and metastasis mediated by mutant p53. Our studies suggest that ATF3 can regulate protein posttranslational modifications and modulate oncogenic signaling via mechanisms independent of its transcriptional activity. While genomics and proteomics approaches are currently utilized to improve our understanding of the ATF3-p53 interaction, we are also exploring the roles of ATF3 in the maintenance of genome stability and tumor suppression using genetically engineered mouse models.

Role of ATF3 in the suppression of prostate cancer.

The growth of prostate cancer cells are dependent on oncogenic signaling mediated by androgen receptor (AR) and PI3K/Akt. We discovered that ATF3 can bind to AR and repress androgen signaling by disrupting the AR intra-molecular interaction and preventing AR from binding to target genes. Using a Pten prostate-specific knockout mouse model, we further found that ATF3 represses Akt signaling and suppresses prostate tumorigenesis induced by common Pten loss. Ongoing studies are designed to further explore the role of ATF3 in prostate cancer, with a special emphasis on castration-resistant prostate cancer growth.

Transcription-targeted anti-cancer therapy.

While transcription is generally considered undruggable due to the lack of interface for targeting by small molecules, we continue our long-time endeavors in the development of effective, cost-efficient platforms for high-throughput searching for transcription-targeted anti-cancer drugs. We apply emerging genome-editing technologies, including the CRISPR/Cas9 system, to develop powerful, bioluminescence-generating reporter assays for large-scale screening for small-molecular drug leads, and collaborate with medicinal chemists to develop these leads into novel anti-cancer agents.  

Wang H, Ma X, Ren S, Boulamwini JK, Yan C. (2011) A small-molecule inhibitor of MDMX activates p53 and induces apoptosis in cancer cells. Mol Cancer Ther 10(1): 69-79

Wang H, Jiang M, Cui H, Chen M, Buttyan R,Hayward S, Hai T, Wang Z, Yan C. (2012) The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor. Mol Cell Biol 32(16): 3190-3202

Wei S, Wang H, Lu C, Malmut S, Zhang J, Ren S, Yu G, Wang W, Tang DD, Yan C. (2014) The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins. J Biol Chem 289(13): 8947-8959

Cui H, Guo M, Xu D, Ding Z, Zhou G, Ding H-F, Zhang J, Tang Y, Yan C. (2015) The stress responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nat Commun 6:6752

Lang L, Ding H-F, Chen X, Sun S-Y, Liu G, Yan C. (2015) Internal ribosome entry site-based bicistronic in situ reporter assays for discovery of transcription-targeted lead compounds. Chem Biol (Cell Chem Biol) 22 (7): 957-964

Wang Z, Xu D, Ding H-F, Kim J, Zhang J, Hai T, Yan C. (2015) Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene 34(38): 4975-4984

Cui H, Li X, Han C, Wang Q-E, Wang H, Ding H-F, Zhang J, Yan C. (2016) The stress responsive gene ATF3 mediates dichotomous UV responses by regulating Tip60 and p53 proteins. J Biol Chem 291 (20): 10847-10857

Wang Z, Kim J, Teng Y, Ding H-F, Zhang J, Hai T, Cowell JK, Yan C. (2016) Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5+CK8+ epithelial cells. Oncogene 35(27): 3555-3564

Zhao J, Li X, Guo M, Yu J, Yan C. (2016) The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation. BMC Genomics 17: 335

Wang Z, He Y, Deng W, Lang L, Yang H, Jin B, Kolhe R, Ding H-F, Zhang J, Hai T, Yan C. (2018) Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice. Oncogene 37 (1): 18-27

Xiaolin Yu - Research Associate