Zhang Chi, Huang Xi, Hu Cheng, Tang Bowen, Wu Jianjie, Sun Zhuolun, Zhu Weian, Zhou Xiangfu, Xiao Hengjun, Wang Hua
Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Oncol Res. 2025 Aug 28;33(9):2331-2351. doi: 10.32604/or.2025.065119. eCollection 2025.
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).
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 and . Additionally, a series of molecular and biochemical assays were performed to investigate the regulatory mechanisms underlying UHMK1 activity.
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.
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.
U2AF同源基序激酶1（UHMK1）与RNA加工和蛋白质磷酸化相关，从而影响肿瘤进展。本研究旨在探讨其在人类前列腺癌（PCa）中的调控机制和生物学功能。
在本研究中，我们系统评估了公共数据库中UHMK1的表达及其预后意义，随后通过免疫组织化学（IHC）在PCa标本中进行验证。进行了功能获得和功能丧失实验以阐明UHMK1的作用。此外，还进行了一系列分子和生化分析以研究UHMK1活性的调控机制。
我们的研究结果显示，通过对公共数据集的分析以及免疫组织化学染色证实，PCa组织中UHMK1表达显著上调，且与患者预后不良相关。功能研究表明，敲低UHMK1可抑制肿瘤细胞增殖和转移，而过表达则促进这些过程。机制上，我们发现UHMK1使核受体共激活因子3（NCOA3）磷酸化，随后激活激活转录因子4（ATF4）以上调亚甲基四氢叶酸脱氢酶2（MTHFD2）的转录。有趣的是，发现MTHFD2可相互增强UHMK1的表达，从而建立一个正反馈环。
总之，我们的数据表明UHMK1-MTHFD2轴形成一个驱动PCa进展的正反馈环。靶向该环代表了一种抑制前列腺癌发生和进展的有前景的治疗策略。
