Chunhong Yan, PhD
Professor, Biochemistry & Molecular Biology
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The Chunhong Yan Lab
Health Sciences Campus
1410 Laney Walker Blvd., CN-2134
(706) 721-0099
The Yan Laboratory is interested in elucidating and therapeutically targeting transcriptional regulatory networks in cancer. We investigate a protein-protein interaction network centered on a common stress-responsive transcription factor ATF3, and aim at understanding how this network regulates the tumor suppressor p53, the cell鈥檚 response to DNA damage and metabolic stress, and the pathways contributing to the development of cancer. We also employ genome-editing tools to build innovative drug-screening platforms for the development of novel therapeutics for advanced cancer.
The tumor suppressor p53 mediates the cellular response to DNA damage, and safeguards the integrity of the genome. The activity of p53 is mainly regulated by MDM2, a E3 ubiquitin ligase which catalyzes ubiquitination and subsequent degradation of the tumor suppressor. While we are the first to demonstrate that ATF3 can regulate cellular functions independent of its transcriptional activity, our research has discovered novel mechanisms mediated by ATF3 that serve to fine tune the p53 activity in response to oncogenic challenges. We found that ATF3 binds both p53 (at the C-terminus) and MDM2 (at the RING domain), and functions as a preferred MDM2 substrate thereby competitively blocking MDM2-mediated ubiquitination and degradation of p53. Our research also unveils that ATF3 can bind Tip60 and stabilize the lysine acetyltransferase, leading to activation of the ATM signaling, which in turn activates p53 in the DNA damage response. Using genetically-engineered mouse models, we demonstrate that Atf3 deficiency promotes genomic instability and spontaneous tumorigenesis in mice. This line of genetic evidence highlights the importance of ATF3 in the regulation of p53 and the DNA damage response.
The growth of prostate cancer cells is dependent on oncogenic signaling mediated by the 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 the suppression of prostate cancer, with a special emphasis on the growth of castration-resistant prostate cancer.
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 developed a toolkit based on the Flp-in technology, and demonstrated its utility in rapid generating bioluminescent reporter assays devoid of epigenetic silencing caused by flanking chromatin. Emerging genome-editing technologies, including the CRISPR/Cas9 system, are also applied to develop more reliable reporter assays for high-throughput drug screening. With these new platforms, we identified one of the first long-sought MDMX (MDM4) inhibitors that can activate p53 for the treatment of cancer. Several other lead compounds targeting Skp2 expression and cell metabolism have also been identified, and undergo further development as novel therapeutics for advanced cancer.
Yan C, Lu D, Hai T, Boyd DD. (2005) EMBO J 24(13): 2425-2435
Yan C, Boyd DD. (2006) Mol Cell Biol 26(17): 6357-6371
Mo P, Wang H, Lu H, Boyd DD, Yan C. (2010) J Biol Chem 285(35): 26908-26915
Wang H, Ma X, Ren S, Boulamwini JK, Yan C. (2011) 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) 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) 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) Nat Commun 6:6752 doi:10.1038/ncomms7752
Lang L, Ding H-F, Chen X, Sun S-Y, Liu G, Yan C. (2015) 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) Oncogene 34(38): 4975-4984
Wang Z, Kim J, Teng Y, Ding H-F, Zhang J, Hai T, Cowell JK, Yan C. (2016) Oncogene 35(27): 3555-3564
Cui H, Li X, Han C, Wang Q-E, Wang H, Ding H-F, Zhang J, Yan C. (2016) J Biol Chem 291 (20): 10847-10857
Zhao J, Li X, Guo M, Yu J *, Yan C. (2016) 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) Oncogene 37(1): 18-27
Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, Ding H-F, Zhang J, Wang H, Chen X, Yan C. (2020) Cell Death Diff 27: 662-675
Li X, Guo M, Cai L, Du T, Liu Y, Ding H-F, Wang H, Zhang J, Chen X, Yan C. (2020) Cell Death Diff 27(6): 1807-1818
Li X, Gracilla D, Cai L, Zhang M, Yu X, Chen X, Zhang J, Long X, Ding H-F, Yan C. (2021) Cell Rep 36(12): 109706
Hawsawi O, Xue W, Du T, Guo M, Yu X, Zhang M, Hoffman PS, Bollag R, Li J, Zhou J, Wang H, Zhang J, Fu Z, Chen X, Yan C. (2025) Cell Rep Med 6(1): 101890
