Citron kinase activity controls alternative splicing events that drive prostate cancer growth.

Authors

Chitra Rawat, Nidhi Singh, Ujjwal R Dahiya, Qiang Hu, Sarah Ng, Dingxiao Zhang, Shaun R Stauffer, Amina Zoubeidi, Eva Corey, Jesse McKenney, Christopher J Weight, Samuel C Haywood, Song Liu, Tao Liu, Hannelore V Heemers

Published in

Science advances. Volume 12. Issue 41. Pages eaee5257. Oct 09, 2026. Epub Oct 09, 2026.

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.

PMID:
42853943
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.