Non-canonical activation of [beta]-catenin by PRL-3 phosphatase in acute myeloid leukemia

• Published in: Oncogene Vol. 38; no. 9; p. 1508
• Main Authors: Chong, Phyllis S. Y, Zhou, Jianbiao, Chooi, Jing-Yuan, Chan, Zit-Liang, Toh, Sabrina Hui Min, Tan, Tuan Zea, Wee, Sheena
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01.02.2019
• Subjects: Acute myelocytic leukemia; Amino acids; Cancer prevention; Care and treatment; Cellular signal transduction; Genetic aspects; Myeloid leukemia; Phosphatases; Risk factors; Serine
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0526-3

Aberrant activation of Wnt/[beta]-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 [beta]-catenin, promoting the nuclear accumulation of [beta]-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 [beta]-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to [beta]-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant [beta]-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 [beta]-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or [beta]-catenin hyperactivation.