Abstract
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.
Highlights
Colorectal cancer (CRC) is the third-leading causes of death, and surgical resection is the standard treatment for early stage CRC [1]
We found that glycogen synthase kinase 3β (GSK-3β), not GSK-α, could bind to and phosphorylate Zinc finger protein 281 (ZNF281) at one consensus motif (TSGEHS; phosphorylation site is shown in italics), which promotes the interaction of ZNF281 with β-transducin repeat-containing protein 2 (β-TrCP2), not β-TrCP1, and leads to the subsequent ubiquitination and degradation of phosphorylated ZNF281
Given that ZNF281 contains a sequence, TSGXXS, which is similar to the DSGXXS/T destruction motif in known substrates of the E3 ligase β-TrCP2 [16], we reasoned that β-TrCP2 might be an upstream regulator of ZNF281
Summary
Colorectal cancer (CRC) is the third-leading causes of death, and surgical resection is the standard treatment for early stage CRC [1]. Efforts to prevent metastasis and increase cure rates after surgery have focused on combined chemotherapy administration [5]. Such therapy is unsatisfactory in reducing metastatic relapse. Growing evidence suggests that transcription factors regulating gene expression and certain signaling pathways during carcinogenesis are potential therapeutic targets because they control tumor initiation and progression [6]. The signaling pathways www.impactjournals.com/oncotarget controlling the expression of these important transcription factors are not yet understood
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