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Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia. (Oncogene, Oct 2018)

Chong PSY1, Zhou J1,2, Chooi JY2, Chan ZL1, Toh SHM1, Tan TZ1, Wee S3, Gunaratne J3,4, Zeng Q3, Chng WJ5,6,7.

Author information
1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3Institute of Molecular and Cell Biology, A*STAR, Singapore.
4Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
5Cancer Science Institute of Singapore, National University of Singapore, Singapore.
6Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore.

Abstract
Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.

PMID: 30305722