The Yan Laboratory

The Yan Laboratory is interested in elucidating and therapeutically targeting aberrant signaling and transcriptional regulatory networks in cancer. We investigate a protein-protein interaction network centered on the common stress-responsive transcription factor ATF3 and aim at understanding how this network regulates the tumor suppressor p53, the cell’s responses to DNA damage and metabolic stress, and pathways contributing to the development of cancer. We also develop novel strategies and small-molecule agents for treating therapy-resistant cancers such as advanced prostate and lung cancer. 

• Regulation of the DNA damage response & DNA repair

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, an E3 ubiquitin ligase that 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 demonstrated that Atf3 deficiency promotes genomic instability and spontaneous tumorigenesis in mice. In addition, we found that ATF3 appears to promote DNA repair. Currently, we are investigating ATF3-mediated regulation of epigenetic modifications of histones at damaged DNA sites to understand how ATF3 facilitates the repair of double-strand DNA breaks caused by carcinogenic and chemotherapeutic agents. These studies would lead to the development of strategies to increase the sensitivity of cancer cells (e.g., lung and prostate cancer cells) to radiation therapy or chemotherapy.

• Metabolic targeting of therapy-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 genome-editing technologies to develop robust, reliable reporter assays for high-throughput drug screening, and identified an FDA-approved anthelmintic drug nitazoxanide that can target mitochondrial homeostasis and subsequently inhibit oncogenic Skp2 expression and E2F1 activity in castration-resistant prostate cancer. We are using clinically relevant mouse models to further investigate the combinational anti-cancer effects of nitazoxanide with conventional therapies, and results would support repositioning this safe drug and its derivatives as novel agents for therapy-resistant prostate cancer.