Phosphorylation-dependent regulation of gene expression and alternative splicing by THRAP3 in prostate cancer

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.