Jianbiao Zhoua, Phyllis SY. Chonga, Xiao Lua, Lip-Lee Cheongb, Chonglei Bia, Shaw-Cheng Liua,Yafeng Zhoua, Tuan Zea Tana, Henry Yanga, Tae-Hoon Chunga, Qi Zengc, and Wee-Joo Chnga,b,d
aCancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore
bDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
cof Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Republic of Singapore
dDepartment of Hematology-Oncology, National University Hospital, Singapore, Republic of Singapore
Overexpression of protein-tyrosine phosphatase of regenerating liver 3 (PRL-3) has been identified in about 50% of patients with acute myeloid leukemia (AML). The mechanism of regulation of PRL-3 remains obscure. Signal transducer and activator of transcription 3 (STAT3), a latent transcriptional factor, has also been often found to be activated in AML. We first identified STAT3-consensus-binding sites in the promoter of PRL-3 genes. Then we experimentally validated the direct binding and transcriptional activation. We applied shRNA-mediated knockdown and overexpression approaches in STAT3L/L liver cells and leukemic cells to validate the functional regulation of PRL-3 by STAT3. A STAT3 core signature, derived through data mining from publicly available gene expression data, was employed to correlate PRL-3 expression in large AML patient samples. We discovered that STAT3 binds to the L201 to L210 region of PRL-3, which was conserved between human and mouse. Importantly, PRL-3 protein was significantly reduced in mouse STAT3-knockout liver cells compared with STAT3–wild type counterparts, and ectopic expression of STAT3 in these cells led to a pronounced increase in PRL-3 protein. We demonstrated that STAT3 functionally regulated PRL-3, and STAT3 core signature was enriched in AML with high PRL-3 expression. Targeting either STAT3 or PRL-3 reduced leukemic cell viability. Silencing PRL-3 impaired invasiveness and induced leukemic cell differentiation. In conclusion, PRL-3 was transcriptionally regulated by STAT3. The STAT3/PRL-3 regulatory loop contributes to the pathogenesis of AML, and it might represent an attractive therapeutic target for antileukemic therapy.
Schematic of the interaction between STAT3 and PRL-3 in contributing to the development and progression of AML.