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miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation

Oncogene volume 36, pages 1023–1037 (2017)Cite this article

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Abstract

During tumourigenesis, p53 functions as 'the guardian of the genome' because p53-dependent apoptosis strongly regulates the fate of cancer cells. Therefore, p53 regulation must be sensitive and accurate. p53 activity is regulated through its ubiquitination and deubiquitination. However, the role of microRNA in ubiquitin-mediated p53 degradation has not been previously studied. Our previous studies indicated that miR-100 is required for apoptosis. In the current study, the mechanism of p53 protein ubiquitination mediated by miR-100 was characterized. An analysis of primary tumour samples from gastric cancer patients showed a significant correlation between miR-100 upregulation and primary human gastric tumourigenesis and progression. The in vivo and in vitro data indicated that miR-100 antagonism specifically induced the apoptosis of poorly differentiated gastric cancer cells but not non-cancerous gastric cells, indicating that miR-100 has a crucial role in regulating the progression of gastric tumours. In the regulation of p53-dependent apoptosis, miR-100 antagonism inhibited ubiquitin-mediated p53 protein degradation by activating RNF144B, an E3 ubiquitination ligase. Consequently, the miR-100-RNF144B-pirh2-p53-dependent pathway was initiated. Our findings highlight a novel mechanism of ubiquitin-mediated p53 protein degradation in apoptosis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (41276152, 31430089) and the National Program on the Key Basic Research Project (2015CB755903).

Author contributions

GY, YG, QZW and LPW performed the experiments. XBZ, GY and YG designed the experiments and analysed the data. YG and XBZ wrote the manuscript. All authors read and approved the contents of the manuscript and its publication.

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Author notes

  1. G Yang and Y Gong: These authors contributed equally to this work.

Authors and Affiliations

  1. Collaborative Innovation Center of Deep Sea Biology and College of Life Sciences, Zhejiang University, Hangzhou, The People’s Republic of China

    G Yang, Y Gong & X Zhang

  2. Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, The People’s Republic of China

    Q Wang & L Wang

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  1. G Yang
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Correspondence to X Zhang.

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Cite this article

Yang, G., Gong, Y., Wang, Q. et al. miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation. Oncogene 36, 1023–1037 (2017). https://doi.org/10.1038/onc.2016.270

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