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MDMX reprograms glycolysis of hepatocellular carcinoma via 14-3-3γ/FOXO1
Han Chen1, Qilong Pan1, Meiqi Mao1
1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Abstract:
MDMX serves as a significant regulator of p53, which is a crucial tumor suppressor protein. However, the biological functions and underlying mechanism of MDMX in hepatocellular carcinoma (HCC) remain inadequately understood. In this study, we demonstrate that MDMX is overexpressed in HCC, and elevated expression of MDMX is significantly correlated with poor prognosis in HCC harboring mutant p53. MDMX inhibits the degradation of 14-3-3γ and facilitates its localization within cytoplasm, thereby enhances the interaction between FOXO1 and 14-3-3γ, which promotes the degradation of FOXO1. Consequently, the overexpression of MDMX results in downregulation of FOXO1 followed by increase of RPIA and decrease of PCK1, leading to increased glucose uptake, lactate secretion, and ATP production. These findings elucidate the role of MDMX in promoting glycolysis through the regulation of the 14-3-3γ/FOXO1 axis in p53-mutated HCC, thereby offering a potential therapeutic target for the treatment of HCC.
Insights
MDMX promotes hepatocellular carcinoma (HCC) progression by increasing glycolysis in p53-mutated tumors. Targeting MDMX could be a therapeutic strategy for HCC patients with poor prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- MDMX (also known as MDM4) is a key regulator of the tumor suppressor p53.
- The specific role and mechanism of MDMX in hepatocellular carcinoma (HCC) are not fully understood.
- p53 mutations are common in HCC, influencing disease progression and treatment response.
Purpose of the Study:
- To investigate the biological functions and molecular mechanisms of MDMX in HCC.
- To determine the correlation between MDMX expression and patient prognosis in HCC, particularly in tumors with p53 mutations.
- To elucidate how MDMX influences cellular metabolism in HCC.
Main Methods:
- Analysis of MDMX expression levels in HCC patient samples.
- Correlation analysis between MDMX expression, p53 mutation status, and patient prognosis.
- Investigation of MDMX's effects on protein degradation pathways, including 14-3-3γ and FOXO1.
- Assessment of metabolic changes, such as glucose uptake, lactate production, and ATP levels, in response to MDMX modulation.
Main Results:
- MDMX is overexpressed in HCC, and high MDMX levels correlate with poor prognosis in HCC patients with mutant p53.
- MDMX inhibits 14-3-3γ degradation and promotes FOXO1 degradation via the 14-3-3γ/FOXO1 axis.
- MDMX overexpression leads to decreased RPIA, increased PCK1, elevated glucose uptake, lactate secretion, and ATP production, indicating promotion of glycolysis.
Conclusions:
- MDMX promotes glycolysis in p53-mutated HCC by regulating the 14-3-3γ/FOXO1 axis.
- MDMX overexpression is linked to a metabolic shift favoring increased glucose utilization and ATP production in HCC.
- MDMX represents a potential therapeutic target for treating HCC, especially in cases with p53 mutations.
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