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The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2.

Publication ,  Journal Article
Yang, W-H; Lin, C-C; Wu, J; Chao, P-Y; Chen, K; Chen, P-H; Chi, J-T
Published in: Mol Cancer Res
June 2021

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. IMPLICATIONS: This study reveals that YAP promotes ferroptosis by regulating SKP2, suggesting novel therapeutic options for YAP-driven tumors.

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Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

June 2021

Volume

19

Issue

6

Start / End Page

1005 / 1014

Location

United States

Related Subject Headings

  • YAP-Signaling Proteins
  • Ubiquitin-Protein Ligases
  • S-Phase Kinase-Associated Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA Interference
  • Oncology & Carcinogenesis
  • MCF-7 Cells
  • Lipid Peroxidation
  • Humans
  • Hippo Signaling Pathway
 

Citation

APA
Chicago
ICMJE
MLA
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Yang, W.-H., Lin, C.-C., Wu, J., Chao, P.-Y., Chen, K., Chen, P.-H., & Chi, J.-T. (2021). The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2. Mol Cancer Res, 19(6), 1005–1014. https://doi.org/10.1158/1541-7786.MCR-20-0534
Yang, Wen-Hsuan, Chao-Chieh Lin, Jianli Wu, Pei-Ya Chao, Kuan Chen, Po-Han Chen, and Jen-Tsan Chi. “The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2.Mol Cancer Res 19, no. 6 (June 2021): 1005–14. https://doi.org/10.1158/1541-7786.MCR-20-0534.
Yang W-H, Lin C-C, Wu J, Chao P-Y, Chen K, Chen P-H, et al. The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2. Mol Cancer Res. 2021 Jun;19(6):1005–14.
Yang, Wen-Hsuan, et al. “The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2.Mol Cancer Res, vol. 19, no. 6, June 2021, pp. 1005–14. Pubmed, doi:10.1158/1541-7786.MCR-20-0534.
Yang W-H, Lin C-C, Wu J, Chao P-Y, Chen K, Chen P-H, Chi J-T. The Hippo Pathway Effector YAP Promotes Ferroptosis via the E3 Ligase SKP2. Mol Cancer Res. 2021 Jun;19(6):1005–1014.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

June 2021

Volume

19

Issue

6

Start / End Page

1005 / 1014

Location

United States

Related Subject Headings

  • YAP-Signaling Proteins
  • Ubiquitin-Protein Ligases
  • S-Phase Kinase-Associated Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA Interference
  • Oncology & Carcinogenesis
  • MCF-7 Cells
  • Lipid Peroxidation
  • Humans
  • Hippo Signaling Pathway