The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase

Molecular Cancer Research : MCR
Liang-Nian SongEdward P Gelmann

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 inhib...Continue Reading

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Citations

Jul 29, 2020·Scientific Reports·ElShaddai Z WhiteCimona V Hinton
Jun 20, 2019·Cancer Research·Cai BowenEdward P Gelmann
Aug 13, 2015·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Brian Thomas JoyceLifang Hou
Jan 29, 2021·World Journal of Stem Cells·Nikolaos Kokkorakis, Maria Gaitanou
Aug 3, 2018·Molecular Therapy. Methods & Clinical Development·Lei ChenYu-Dong Cai
Jun 3, 2021·Cancers·Moloud A SooreshjaniKavita Shah
Oct 10, 2021·Journal of Biomedical Science·Moloud Aflaki SooreshjaniKavita Shah

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