TRIM37 Augments AP-2γ Transcriptional Activity and Cellular Localization via K63-linked Ubiquitination to Drive Breast Cancer Progression
Guimei Cui, Zhuoran Gao, Shiehong Chang, Nitin Narwade, Yitian Chen, Barun Poudel, Kate M. K. Lei, Weibo Zhang, Gang Li, Terence Chuen Wai Poon, Edwin Cheung
Abstract
Activator Protein 2 gamma (AP-2γ) is a master transcription factor that plays a critical role in the development and progression of breast cancer. However, the underlying mechanism is still unclear. Herein, using a proteomics approach, we identified Tripartite motif-containing 37 (TRIM37) as a novel coactivator of AP-2γ-mediated transcription in breast cancer cells. We demonstrate that TRIM37 facilitates AP-2γ chromatin binding to directly regulate the AP-2γ mediated transcriptional program. We also show that TRIM37 achieves this by stimulating K63 chain-linked ubiquitination of AP-2γ, promoting protein localization from the cytoplasm to the nucleus. In clinical analyses, we find TRIM37 is upregulated in multiple breast cancer datasets, supporting our findings that the TRIM37-AP-2γ interaction is essential for breast cancer tumor growth. Overall, our work reveals that TRIM37 is an oncogenic coactivator of AP-2γ in breast cancer and provides a novel therapeutic target for treating the disease.