The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2
Abstract
Ferroptosis is a new form of regulated cell death resulting from the accumulation of lipid-reactive oxygen species. A growing number of studies indicate ferroptosis as an important tumor suppressor mechanism having therapeutic potential in cancers. Previously, we identified TAZ, a Hippo pathway effector, regulates ferroptosis in renal and ovarian cancer cells. Because YAP (Yes-associated protein 1) is the one and only paralog of TAZ, sharing high sequence similarity and functional redundancy with TAZ, we tested the potential roles of YAP in regulating ferroptosis. Here, we provide experimental evidence that YAP removal confers ferroptosis resistance, whereas overexpression of YAP sensitizes cancer cells to ferroptosis. Furthermore, integrative analysis of transcriptome reveals S-phase kinase-associated protein 2 (SKP2), an E3 ubiquitin ligase, as a YAP direct target gene that regulates ferroptosis. We found that the YAP knockdown represses the expression of SKP2. Importantly, the genetic and chemical inhibitions of SKP2 robustly protect cells from ferroptosis. In addition, knockdown of YAP or SKP2 abolishes the lipid peroxidation during erastin-induced ferroptosis. Collectively, our results indicate that YAP, similar to TAZ, is a determinant of ferroptosis through regulating the expression of SKP2. Therefore, our results support the connection between Hippo pathway effectors and ferroptosis with significant therapeutic implications.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 11, 2021
- Source ID
- 10.1158/1541-7786.mcr-20-0534
Entities
People
- Chao-Chieh Lin
- Jen-Tsan A Chi
- Jianli Wu
- Kuan Chen
- Pei-ya Chao
- Po-Han Chen
- Wen-Hsuan Yang
Organizations
- Duke University
- United States Department of Defense