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DNA Hypermethylation-induced LRRC4 downregulation: a driver of glycolysis and lung adenocarcinoma progression
Xudong Wei1, Guangcheng Yue1, Xiaodong Zheng1
1Thoracic Surgery Department, Anyang Tumor Hospital, No. 1 Huanbin North Road, Anyang 455000, Henan, China.
Background:
Lung adenocarcinoma (LUAD) remains a significant health threat, with high incidence and mortality rates that necessitate innovative treatment strategies. A critical step forward is to elucidate the molecular mechanisms driving LUAD progression. Although LRRC4 has been well-documented as a tumor suppressor in gliomas, its role in LUAD remains largely unknown, suggesting a need for further investigation.
Methods:
In LUAD and normal tissues, LRRC4 expression were examined using TCGA data. Methylation differences were assessed using the MethylMix package, and CpG island distribution in the LRRC4 promoter was predicted with MethPrimer. Gene set enrichment analysis (GSEA) was performed to identify pathways associated with LRRC4 and its correlation with key glycolytic genes. LRRC4 mRNA levels were measured by qPCR, and protein expression was detected by western blot for LRRC4 and glycolysis-related proteins. Methylation-specific PCR (MSP) was used to analyze methylation status in normal and LUAD cells. Cellular functions, specifically viability, proliferation, and invasiveness, were evaluated via CCK-8, colony formation, and Transwell assays. Glycolytic activity was determined through glucose consumption, lactate production, ATP levels, and Seahorse XF analysis.
Results:
LRRC4 was steeply downregulated in LUAD, with a strong negative correlation between its expression and methylation levels. Multiple CpG sites were identified in the promoter region, and MSP demonstrated higher methylation in LUAD cells compared to normal cells. Functionally, LRRC4 acted as a suppressor of LUAD cell viability, proliferation, and invasiveness. GSEA indicated that LRRC4 was enriched in the glycolysis pathway and negatively correlated with key glycolytic genes. LRRC4 also inhibited glucose consumption, lactate and ATP production, and facilitated a metabolic shift toward oxidative phosphorylation.
Conclusion:
Promoter hypermethylation of LRRC4 triggers its downregulation, which promotes glycolysis and fuels the aggressive progression of LUAD.
Insights
Leucine-rich repeat-containing protein 4 (LRRC4) acts as a tumor suppressor in lung adenocarcinoma (LUAD). Promoter hypermethylation downregulates LRRC4, promoting glycolysis and aggressive LUAD progression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lung adenocarcinoma (LUAD) presents a significant global health challenge.
- Understanding LUAD molecular mechanisms is crucial for developing novel treatments.
- The tumor suppressor role of LRRC4 in gliomas is established, but its function in LUAD is largely unexplored.
Purpose of the Study:
- To investigate the role of LRRC4 in lung adenocarcinoma.
- To determine the impact of LRRC4 expression and methylation on LUAD progression.
- To elucidate the relationship between LRRC4 and cellular metabolism in LUAD.
Main Methods:
- Analysis of LRRC4 expression and methylation in LUAD tissues using TCGA data.
- Assessment of LRRC4 promoter methylation using MethylMix and MSP.
- Evaluation of LUAD cell functions (viability, proliferation, invasiveness) and glycolytic activity.
- Correlation analysis between LRRC4 and key glycolytic genes via GSEA.
Main Results:
- LRRC4 expression is significantly downregulated in LUAD, inversely correlated with promoter methylation.
- LRRC4 suppresses LUAD cell viability, proliferation, and invasiveness.
- LRRC4 downregulation is linked to the glycolysis pathway and promotes glucose consumption, lactate production, and ATP levels.
Conclusions:
- Promoter hypermethylation is a key mechanism for LRRC4 downregulation in LUAD.
- Downregulated LRRC4 promotes glycolysis, contributing to aggressive LUAD progression.
- LRRC4 functions as a tumor suppressor in LUAD by inhibiting glycolysis.
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