Open Access

ARTICLE

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

Chi Zhang^1,#, Xi Huang^2,#, Cheng Hu¹, Bowen Tang¹, Jianjie Wu¹, Zhuolun Sun¹, Weian Zhu¹, Xiangfu Zhou¹, Hengjun Xiao^1,*, Hua Wang^1,*

1 Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
2 Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

* Corresponding Authors: Hengjun Xiao. Email: ; Hua Wang. Email:
# These two authors contributed equally to this work

(This article belongs to the Special Issue: Novel Biomarkers and Treatment Strategies in Solid Tumor Diagnosis, Progression, and Prognosis)

Oncology Research 2025, 33(9), 2331-2351. https://doi.org/10.32604/or.2025.065119

Received 04 March 2025; Accepted 09 July 2025; Issue published 28 August 2025

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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Supplementary Material

Supplementary Material File

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