Phosphorylation-dependent THRAP3 RNA-binding in prostate cancer

ABSTRACT: Prostate cancer (CaP) is a leading cause of cancer deaths in American men. Searching for novel treatments, we uncovered a critical role for the poorly characterized mitotic citron kinase (CIT) in CaP growth and tumorigenicity. CIT’s effects on CaP cells relied entirely on its kinase activity. However, selective CIT inhibitors are not yet available. Therefore, we defined CIT kinase’s substrates and examined the potential of their action for therapeutic intervention. We previously reported that over half of CIT’s substrates are involved in alternative splicing that is enriched in treatment-resistant CaP. Here, we focus on Thyroid Hormone Receptor-Associated Protein 3 (THRAP3), an RNA-binding protein implicated in mRNA splicing, stability, and DNA damage response that our prior studies identified as a CIT substrate. THRAP3 silencing and overexpression diminished and increased, respectively, CaP cell proliferation, mimicking CIT’s effects. By performing CLIP-Seq assay, we identified several hundreds of CIT-dependent THRAP3-bound transcripts, which were also enriched for functions in cell proliferation. Overexpression of CIT-induced THRAP3-bound transcripts promoted growth of CaP cell lines, organoids and xenografts. These findings define a novel mechanism by which CIT rewires alternative splicing in CaP and present new therapeutic opportunities for targeting aggressive CaP.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310293 | GEO | 2026/08/25

REPOSITORIES: GEO