• Biologie

  • Oncogènes et suppresseurs de tumeurs

  • Prostate

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

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en accélérant la dégradation du suppresseur de tumeurs NKX3.1, la kinase DYRK1B favorise la croissance d'une tumeur de la prostate

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. Since NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high throughput screen was developed using a 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 serine185, 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. Implications: DYRK1B is a promising and novel kinase target for prostate cancer treatment mediated by enhancing NKX3.1 levels.

Molecular Cancer Research

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