PLK1 and Smad4 are two important factors in prostate cancer initiation and progression. They have been reported to play the opposite role in Pten-deleted mice, one is an oncogene, the other is a tumor suppressor. Moreover, they could reversely regulate the PI3K/AKT/mTOR pathway and the activation of MYC. However, the connections between PLK1 and Smad4 have never been studied. Here, we showed that PLK1 could interact with Smad4 and promote the ubiquitination and degradation of Smad4 in PCa cells. PLK1 and PELO could bind to different domains of Smad4 and formed a protein complex. PELO facilitated the degradation of Smad4 through cooperating with PLK1, thereby resulting in proliferation and metastasis of prostate cancer cell. Changes in protein levels of Smad4 led to the alteration of biological function that caused by PLK1 in prostate cancer cells. Further studies showed that PELO upregulation was positively associated with high grade PCa and knockdown of PELO expression significantly decreased PCa cell proliferation and metastasis in vitro and vivo. PELO knockdown in PCa cells could enhance the tumor suppressive role of PLK1 inhibitor. In addition, blocking the interaction between PELO and Smad4 by using specific peptide could effectively inhibit PCa cell metastasis ability in vitro and vivo. Overall, these findings identified a novel regulatory relationship among PLK1, Smad4 and PELO, and provided a potential therapeutic strategy for advanced PCa therapy by co-targeting PLK1 and PELO.
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We thank the College of Life Sciences at Shaanxi Normal University for the sharing platform of laboratory apparatus. This work was funded by the National Natural Science Foundation of China (81972417), The “1000 Young Scholars” Program of Shaanxi Province, Natural Science Foundation of Shaanxi Province (2020JM-292, 2020JQ-430), Fundamental Research Funds for the Central Universities (GK201902002, GK201903061) and College Students’ Innovative Entrepreneurial Training Plan Program (S202110718036).
The authors declare no competing interests.
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Gao, P., Hao, JL., Xie, QW. et al. PELO facilitates PLK1-induced the ubiquitination and degradation of Smad4 and promotes the progression of prostate cancer. Oncogene 41, 2945–2957 (2022). https://doi.org/10.1038/s41388-022-02316-8