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Cancer Res. 2018 Mar 1;78(5):1214-1224. doi: 10.1158/0008-5472.CAN-17-3512. Epub 2018 Jan 4.

O-GlcNAcylation of the Tumor Suppressor FOXO3 Triggers Aberrant Cancer Cell Growth.

Author information

1
Yonsei Proteome Research Center, Yonsei University, Seoul, Republic of Korea.
2
Graduate program in Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea.
3
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
4
Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
5
Yonsei Proteome Research Center, Yonsei University, Seoul, Republic of Korea. paikyk@yonsei.ac.kr.
6
Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.

Abstract

Posttranslational modifications of tumor suppressors can induce abnormal cell growth. Here, we identify site-specific O-GlcNAcylation as a critical block of FOXO3 that may abrogate a part of the p53 pathway, resulting in aberrant cancer cell growth. Of seven O-GlcNAcylation sites identified within the FOXO3 transactivation domain, we found that changes in O-GlcNAcylation at Ser284 modulated p21-mediated cancer cell growth. Overexpression of either O-GlcNAcylated FOXO3 (FOX-OV) or a Ser-to-Ala mutant (S284A) in PANC-1 cells indicated that S284 O-GlcNAc acts as a critical block of the FOXO tumor suppressor and induces proliferation in PANC-1 cancer cells by stimulating the MDM2-p53-p21 axis. Furthermore, S284A mutant cells lacking S284 O-GlcNAc and FOX-OV cells exhibited opposing MDM2-p53-p21 axis expression patterns at both the mRNA and protein levels. Thus, our study provides evidence to support a role for S284 O-GlcNAc as a critical block of FOXO3 to induce subsequent cancer cell growth via abrogation of the p53 regulatory circuit.Significance: These findings highlight a posttranslational mechanism for indirect abrogation of the p53 pathway, one that may occur with some frequency in human cancer cells. Cancer Res; 78(5); 1214-24. ©2018 AACR.

PMID:
29301793
DOI:
10.1158/0008-5472.CAN-17-3512
[Indexed for MEDLINE]

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