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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• U2AF homology motif kinase 1 (UHMK1) is implicated in RNA processing and protein phosphorylation, influencing tumor progression.
• Its role in human prostate cancer (PCa) warrants further investigation into its regulatory mechanisms and biological functions.

Purpose of the Study:

• To explore the regulatory mechanisms and biological functions of UHMK1 in prostate cancer.
• To evaluate the expression and prognostic significance of UHMK1 in PCa.
• To investigate the molecular pathways driving UHMK1 activity in PCa.

Main Methods:

• Systematic evaluation of UHMK1 expression and prognostic significance in public databases.
• Immunohistochemistry (IHC) validation in PCa specimens.
• In vitro and in vivo gain-of-function and loss-of-function experiments.
• Molecular and biochemical assays to determine UHMK1 regulatory mechanisms.

Main Results:

• UHMK1 is significantly upregulated in PCa tissues, correlating with poor prognosis.
• UHMK1 depletion suppresses, while overexpression promotes, PCa cell proliferation and metastasis.
• UHMK1 phosphorylates NCOA3, activating ATF4 and upregulating MTHFD2 transcription.
• MTHFD2 reciprocally enhances UHMK1 expression, forming a positive feedback loop.

Conclusions:

• The UHMK1-MTHFD2 axis forms a positive feedback loop driving PCa progression.
• Targeting this axis presents a promising therapeutic strategy for prostate cancer.
• Understanding this pathway could lead to novel treatments for PCa.