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Natural compound PEITC inhibits gain of function of p53 mutants in cancer cells by switching YAP-binding partners between p53 and p73

Acta Pharmacologica Sinica volume 46, pages 1722–1732 (2025)Cite this article

Abstract

Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables has shown anticancer activities by modulating apoptosis, cell cycle arrest, drug-metabolizing enzymes and even preferentially restoring a ‘WT-like’ conformation to p53R175H. But its molecular anti-cancer mechanisms are not well understood. Evidence shows that switching YAP-binding partners from pro-tumorigenic to pro-apoptotic proteins might hold great potential for the treatment of human cancers harboring mtp53. In this study we investigated the impact of PEITC on mtp53-YAP-p73 interaction in cancers harboring a variety of p53 mutants, but not limited to structural mutations. We showed that breast cancer, colorectal and lung cancer cells harboring mtp53 (p53R280K, p53R273H) were more sensitive to PEITC than those cells harboring wtp53. We demonstrated that PEITC bound to YAP at its WW binding domain, and induced a conformational change, facilitated the dissociation of YAP-mtp53 complex and inhibited their pro-proliferative transcriptional activity in different cancer cells harboring mtp53. Concomitantly, PEITC acted as a molecular glue to enhance the association of YAP-p73 complex and induced apoptosis. These results provide insights into the anticancer activity of PEITC against a wide spectrum of cancers and highlight a unique mode of action for PEITC-based cancer therapy.

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Fig. 1: Cancer cells harboring mtp53 are more sensitive to PEITC than those harboring wtp53.
Fig. 2: Cancer cells harboring mtp53 are more susceptible to PEITC-induced apoptosis than those harboring wtp53.
Fig. 3: PEITC binds YAP at its WW domain.
Fig. 4: PEITC facilitates dissociation of the YAP-mtp53 complex.
Fig. 5: PEITC promotes association of the YAP-p73 complex.
Fig. 6: PEITC acts a molecular glue to facilitate association of the YAP-p73 complex.

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Data availability

Data generated in this study are available upon reasonable request from the corresponding authors.

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Acknowledgements

We thank Dian-hua Chen (School of Life Sciences, Nanjing University) for technological assistance.

Funding

This work was supported by National Natural Science Foundation of China (Grant Nos. 81974504, 82230116), National Key R&D Program of China (Grant No. 2022YFC3500202), and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202208).

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  1. These authors contributed equally: Yi-xuan Wang, Li-wei Wang

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China

    Yi-xuan Wang, Li-wei Wang, Ying Huang, Lin Zhou, Guo-yu Li, Jia-wen Yang, Xue-feng Wu, Qiang Xu & Yan Shen

  2. Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China

    Yi-xuan Wang

  3. Drug R&D Institute, JC (Wuxi) Company Inc., Wuxi, 214000, China

    Jing-cai Cheng

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Contributions

YS and QX designed this study; YXW, LWW, YH, LZ and GYL performed research; YXW, LWW, JWY analyzed data; JCC and XFW contributed to the discussion; YXW, LWW and YS wrote the manuscript.

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Correspondence to Jing-cai Cheng, Qiang Xu or Yan Shen.

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Jing-cai Cheng was in  Drug R&D Institute, JC (Wuxi) Company Inc. He declares no competing interests.

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Wang, Yx., Wang, Lw., Huang, Y. et al. Natural compound PEITC inhibits gain of function of p53 mutants in cancer cells by switching YAP-binding partners between p53 and p73. Acta Pharmacol Sin 46, 1722–1732 (2025). https://doi.org/10.1038/s41401-025-01474-1

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