title: Phosphatase of regenerating liver-3 is regulated by signal transducer and activator of transcription 3 in acute myeloid leukemia.
abstract: 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 STAT3(-/-) 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 -201 to -210 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Phyllis S Y
authors.initials: PS
authors.lastname: Chong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Lip-Lee
authors.initials: LL
authors.lastname: Cheong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Shaw-Cheng
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Chung
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Republic of Singapore.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Department of Hematology-Oncology, National University Hospital, Singapore, Republic of Singapore. Electronic address: mdccwj@nus.edu.sg.
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D013045:Species Specificity; D014162:Transfection
chemical_list: D004273:DNA, Neoplasm; D017874:Immediate-Early Proteins; D009363:Neoplasm Proteins; C111534:Ptp4a3 protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases