UHMK1 Promotes Prostate Cancer Progression through a Positive Feedback Loop with MTHFD2

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Abstract
Background: U2AF homology motif kinase 1 (UHMK1) has been associated with RNA processing and protein phosphorylation, thereby influencing tumor progression. The study aimed to explore its regulatory mechanisms and biological functions in human prostate cancer (PCa). Methods: In this study, we systematically evaluated the expression and prognostic significance of UHMK1 in public databases, followed by validation through immunohistochemistry (IHC) in PCa specimens. Both gain-of-function and loss-of-function experiments were conducted to elucidate the role of UHMK1 in vitro and in vivo. Additionally, a series of molecular and biochemical assays were performed to investigate the regulatory mechanisms underlying UHMK1 activity. Results: Our findings revealed that UHMK1 expression was significantly upregulated in PCa tissues and correlated with poor patient prognosis, as demonstrated by analysis of public datasets and confirmed by immunohistochemical staining. Functional studies showed that UHMK1 depletion suppressed tumor cell proliferation and metastasis, while its overexpression promoted these processes. Mechanistically, we identified that UHMK1 phosphorylates nuclear receptor coactivator 3 (NCOA3), which subsequently activates activating transcription factor 4 (ATF4) to upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) transcription. Interestingly, MTHFD2 was found to reciprocally enhance UHMK1 expression, establishing a positive feedback loop. Conclusions: In conclusion, our data suggest that the UHMK1-MTHFD2 axis forms a positive feedback loop that drives PCa progression. Targeting this loop represents a promising therapeutic strategy for restraining prostate cancer development and progression.

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