Citron kinase activity controls alternative splicing events that drive prostate cancer growth
10 affiliations
- 1Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA.
- 2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14623, USA.
- 3Case Western Reserve University, Cleveland, OH 44106, USA.
- 4School of Biomedical Sciences, Hunan University, Changsha 410082, China.
- 5Center for Therapeutics Discovery, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA.
- 6Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
- 7Department of Urology, University of Washington, Seattle, WA 98195, USA.
- 8Department of Anatomic Pathology, Diagnostics Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
- 9Department of Urology, Integrated Surgical Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
- 10Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Abstract
Prostate cancer (CaP) remains a major cause of cancer death in men, underscoring the need for mechanistically novel therapies. We previously identified the action of the mitotic kinase citron (CIT) kinase as a key driver of CaP progression and promising therapeutic target, but selective CIT inhibitors are not available. We therefore asked whether a better understanding of the action of CIT substrates, which execute CIT kinase action in CaP cells, can lead to novel approaches and/or alternative targets to indirectly interfere with CIT's activity during CaP progression. In view of the enrichment in functions in alternative splicing among CIT substrates, we focus on the RNA splicing regulator THRAP3 as a representative substrate. Direct THRAP3 phosphorylation by CIT determined THRAP3's RNA binding to CIT-controlled pre-messenger RNA targets. Cross-linking and immunoprecipitation sequencing identified a subset of CIT-dependent THRAP3-bound genes that were preferentially involved in cell proliferation. THRAP3 RNA binding was enriched in genes that undergo alternative splicing during CaP progression. CIT-dependent THRAP3-bound transcripts stimulated the growth of CaP cell lines, xenografts, patient-derived organoids, and patient-derived xenograft (PDX)-derived organoids, whereas CIT-independent THRAP3-bound transcripts from the same gene did not. An antisense oligo that blocks THRAP3's recruitment to a CIT-dependent RNA binding site prevented the production of CIT- and THRAP3-dependent transcripts and inhibited the growth of cell lines and PDX-derived organoids representing different CaP stages and lineages but not of benign cells. Thus, CIT-mediated alternative splicing drives CaP progression, and its inhibition is a new therapeutic strategy in treatment-resistant CaP.
Related
- Exploration of Alternative Approaches to Citron Kinase Inhibition for Glioblastoma Treatment
- Alternative splicing of a species- and skeletal muscle-specific microexon diversifies the menu of clathrin heavy chains in mice and rats
- G-Quadruplexes at the ‘Interface’ of Transcription and Alternative Splicing
- SRSF1 coordinates transcription and alternative splicing to modulate p53 and genome-maintenance
- FET fusion proteins reshape splicing factor networks to drive oncogenic alternative splicing
BibTeX
@article{rawat2026citron,
title = {{Citron kinase activity controls alternative splicing events that drive prostate cancer growth}},
author = {Chitra Rawat and Nidhi Singh and Ujjwal R. Dahiya and Qiang Hu and Sarah Ng and Dingxiao Zhang and Shaun R. Stauffer and Amina Zoubeidi and Eva Corey and Jesse McKenney and Christopher J. Weight and Samuel C. Haywood and Song Liu and Tao Liu and Hannelore V. Heemers},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aee5257},
url = {https://www.science.org/doi/10.1126/sciadv.aee5257},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Citron kinase activity controls alternative splicing events that drive prostate cancer growth
AU - Chitra Rawat
AU - Nidhi Singh
AU - Ujjwal R. Dahiya
AU - Qiang Hu
AU - Sarah Ng
AU - Dingxiao Zhang
AU - Shaun R. Stauffer
AU - Amina Zoubeidi
AU - Eva Corey
AU - Jesse McKenney
AU - Christopher J. Weight
AU - Samuel C. Haywood
AU - Song Liu
AU - Tao Liu
AU - Hannelore V. Heemers
PY - 2026
DA - 2026/10/09
JO - Science Advances
DO - 10.1126/sciadv.aee5257
UR - https://www.science.org/doi/10.1126/sciadv.aee5257
AB - Prostate cancer (CaP) remains a major cause of cancer death in men, underscoring the need for mechanistically novel therapies. We previously identified the action of the mitotic kinase citron (CIT) kinase as a key driver of CaP progression and promising therapeutic target, but selective CIT inhibitors are not available. We therefore asked whether a better understanding of the action of CIT substrates, which execute CIT kinase action in CaP cells, can lead to novel approaches and/or alternative targets to indirectly interfere with CIT's activity during CaP progression. In view of the enrichment in functions in alternative splicing among CIT substrates, we focus on the RNA splicing regulator THRAP3 as a representative substrate. Direct THRAP3 phosphorylation by CIT determined THRAP3's RNA binding to CIT-controlled pre-messenger RNA targets. Cross-linking and immunoprecipitation sequencing identified a subset of CIT-dependent THRAP3-bound genes that were preferentially involved in cell proliferation. THRAP3 RNA binding was enriched in genes that undergo alternative splicing during CaP progression. CIT-dependent THRAP3-bound transcripts stimulated the growth of CaP cell lines, xenografts, patient-derived organoids, and patient-derived xenograft (PDX)-derived organoids, whereas CIT-independent THRAP3-bound transcripts from the same gene did not. An antisense oligo that blocks THRAP3's recruitment to a CIT-dependent RNA binding site prevented the production of CIT- and THRAP3-dependent transcripts and inhibited the growth of cell lines and PDX-derived organoids representing different CaP stages and lineages but not of benign cells. Thus, CIT-mediated alternative splicing drives CaP progression, and its inhibition is a new therapeutic strategy in treatment-resistant CaP.
SN - 2375-2548
ER -