Research Papers:

GSK-3β phosphorylation-dependent degradation of ZNF281 by β-TrCP2 suppresses colorectal cancer progression

Yuekun Zhu, Qingxin Zhou, Guiling Zhu, Yanwei Xing, Shiqiang Li, Niansheng Ren, Tianyou Liu, Anlong Zhu, Yuxian Bai and Daxun Piao _

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Oncotarget. 2017; 8:88599-88612. https://doi.org/10.18632/oncotarget.20100

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Yuekun Zhu1,*, Qingxin Zhou2,*, Guiling Zhu1, Yanwei Xing1, Shiqiang Li1, Niansheng Ren1, Tianyou Liu1, Anlong Zhu1, Yuxian Bai2 and Daxun Piao1

1Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China

2Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin 150086, Heilongjiang Province, China

*These authors have contributed equally to this work

Correspondence to:

Daxun Piao, email: [email protected]

Qingxin Zhou, email: [email protected]

Keywords: colorectal cancer, zinc finger protein 281, the β-transducin repeat-containing protein 2, glycogen synthase kinase 3β, ubiquitination

Received: May 24, 2017     Accepted: July 13, 2017     Published: August 09, 2017


Zinc finger protein 281 (ZNF281) has been recently shown to be critical for CRC progression. However, the immediate upstream regulators of ZNF281 remain unclear. Here we reported that the E3 ligase the β-transducin repeat-containing protein 2 (β-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous β-TrCP2 were inversely correlated with ZNF281. Beta-TrCP2 reversed the phenotype of CRC cell with overexpressed ZNF281. Moreover, we found that glycogen synthase kinase 3β (GSK-3β), not GSK-α, could bind to and phosphorylate ZNF281 at one consensus motif (TSGEHS; phosphorylation site is shown in italics), which promotes the interaction of ZNF281 with β-TrCP2, not β-TrCP1, and leads to the subsequent ubiquitination and degradation of phosphorylated ZNF281. A mutant of ZNF281 (ZNF281-S638A) is much more stable than wild-type ZNF281 because ZNF281-S638A mutant abolishes the phosphorylation by GSK-3β and can not be ubiquitinated and degraded by β-TrCP2. Conversely, ZNF281 transcriptionally repressed the expression of β-TrCP2, indicating a negative feedback loop between ZNF281 and β-TrCP2 in CRC cells. These findings suggest that the turnover of ZNF281 by β-TrCP2 might provide a potentially novel treatment for patients with CRC.

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