O-GlcN acylation of the tumor suppressor FOXO3 triggers aberrant cancer cell growth

Heon Shin, Hyun Jeong Cha, Keun Na, Min Jung Lee, Jin Young Cho, Chae Yeon Kim, Eun Kyung Kim, Chang Moo Kang, Hoguen Kim, Young Ki Paik

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5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1214-1224
Number of pages11
JournalCancer Research
Volume78
Issue number5
DOIs
Publication statusPublished - 2018 Mar 1

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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