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Phosphorylation-dependent regulation of gene expression and alternative splicing by THRAP3 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. Thyroid Hormone Receptor-Associated Protein 3 (THRAP3) is 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. We then identified the several THRAP3-bound transcripts, one of which is CPT1A. CPT1A was found to be alternatively spliced by THRAP3 in prostate cancer cells generating a catalytically inactive, alternatively spliced variant, CPT1A-v2, while having no effect on the conventional active variant, CPT1A-v1. We demonstrate the therapeutic potential of disrupting the THRAP3-RNA binding via RNA decoys and antisense oligonucleotides (ASOs) which resulted in reduced synthesis of the oncogenic variant of CPT1A-v2 and thereby reduced growth of prostate cancer cells and patient-derived organoids (PDOs). In addition, overexpression of the oncogenic splice variant, CPT1A-v2 increased the prostate cancer cell growth, xenograft tumor volume and PDO growth, while CPT1A-v2 overexpression had either no or opposite effects. Targeting the synthesis of such variants by disrupting the THRAP3-RNA binding, therefore, may provide fresh therapeutic perspectives. 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: GSE333837 | GEO | 2026/08/25

REPOSITORIES: GEO

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Phosphorylation-dependent THRAP3 RNA-binding in prostate cancer

Project description: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.

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