The RNA-binding protein KHSRP drives prostate cancer progression through a DUSP6 dependent axis

Prostate cancer (PCa) remains a major clinical challenge, particularly because of its progression to more aggressive disease states, and the molecular mechanisms driving its progression are still incompletely understood. KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein involved in post-transcriptional gene regulation, but its role and downstream regulatory mechanisms in PCa remain unclear. The clinical relevance of KHSRP in PCa was assessed using public datasets and patient specimens. We assessed the biological functions of KHSRP in vitro and in vivo, identified DUSP6 by integrative RNA-seq and RIP-seq analyses, and further validated the associated signaling and phenotypic changes using Western blotting and functional assays. KHSRP was significantly upregulated in PCa and was associated with aggressive clinicopathological features and poor prognosis. Functional experiments showed that KHSRP overexpression promoted proliferation, migration, and invasion while suppressing apoptosis in PCa cells, whereas KHSRP knockdown produced the opposite effects. Mechanistically, integrative RNA-seq and RIP-seq analyses identified DUSP6 as a candidate downstream target of KHSRP. Further validation using RNA immunoprecipitation assays and RNA decay assays demonstrated that KHSRP accelerated DUSP6 mRNA decay and repressed DUSP6 expression at the post-transcriptional level. Reduced DUSP6 expression was accompanied by enhanced ERK phosphorylation and coordinated activation of PI3K/AKT/mTOR signaling. Restoration of DUSP6 attenuated the pro-tumorigenic effects of KHSRP and weakened the associated signaling activation. Xenograft assays further confirmed the tumor-promoting role of KHSRP in vivo. KHSRP drives PCa progression through a DUSP6-dependent signaling axis by repressing DUSP6 at the post-transcriptional level and facilitating coordinated activation of ERK and PI3K/AKT/mTOR signaling. These findings identify a previously unrecognized KHSRP–DUSP6 regulatory axis in PCa and suggest that KHSRP may serve as a potential therapeutic target.