title: The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase.
abstract: NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was developed using an siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates, of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover. Lastly, small-molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1.
  
  
  CONCLUSIONS
  DYRK1B is a promising and novel kinase target for prostate cancer treatment mediated by enhancing NKX3.1 levels.
authors.affiliation: Departments of Medicine and Pathology, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Song
authors.affiliation: Icahn, New York, New York.
authors.forename: Jose
authors.initials: J
authors.lastname: Silva
authors.affiliation: Proteomics Shared Resource at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Antonius
authors.initials: A
authors.lastname: Koller
authors.affiliation: NIH Chemical Genomics Center, Bethesda, Maryland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Proteomics Shared Resource at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York. Department of Pharmacology, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.affiliation: Departments of Medicine and Pathology, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Gelmann
mesh_terms: D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D000097603:Dyrk Kinases
chemical_list: D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D014157:Transcription Factors; D000097603:Dyrk Kinases; C491178:NKX3-1 protein, human