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RAD21 reshapes H3K4me3 modification to drive lung adenocarcinoma progression by activating ERK1/2 signal [ChIP-seq]

ABSTRACT: RAD21, the core unit of the cohesin complex, is involved in the transcriptional regulation of cells. The high-frequency copy number amplification of RAD21 is general in multiple cancer types and positively correlated with high mRNA levels, such as lung adenocarcinoma (LUAD). However, its role in LUAD is unclear. We found that RAD21 is a poor prognostic factor for LUAD patients. Functionally, depletion of RAD21 using shRNAs impairs LUAD cell proliferation and metastatic ability. Transcriptome sequencing reveals that RAD21 loss inactivates epithelial-mesenchymal transition (EMT) and MAPK signaling pathways in LUAD cell lines, which can be rescued by exogenous RAD21. Pharmacologic ERK1/2 inhibition with specific inhibitor ulixertinib exhibits superior repression on the RAD21-driven high metastatic ability. Clinical exploration using specimens from LUAD patients further validates the correlation between RAD21 and the ERK1/2-EMT process. Taken together, our work reveals the regulatory relationship between RAD21-mediated epigenetic regulation and metastasis signaling cascade in LUAD. The favorable therapeutic efficacy of ulixertinib in mouse models with lung metastasis provides a therapeutic rationale for ERK1/2 inhibition in RAD21-high LUAD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294136 | GEO | 2026/08/01

REPOSITORIES: GEO

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Project description:Metastasis remains the leading cause of mortality in lung adenocarcinoma (LUAD), yet the molecular mechanisms driving metastatic progression, particularly to the liver, remain incompletely understood. Metabolic reprogramming has emerged as a hallmark of cancer, but how amino acid transport interfaces with lipid metabolism to regulate metastasis is poorly defined. We integrated bioinformatic analysis of The Cancer Genome Atlas (TCGA) LUAD cohort with in vitro and in vivo functional studies. Weighted gene co-expression network analysis (WGCNA) was performed to identify metastasis-associated modules. SLC7A5 function was evaluated using knockdown approaches in LUAD cell lines, assessed by Western blot, wound healing, Transwell migration assays, and an orthotopic lung cancer mouse model. Mechanistic studies included RNA-seq, targeted fatty acid profiling, BODIPY FL C16 uptake assays, Seahorse FAO analysis, and PPARA luciferase reporter assays. WGCNA identified SLC7A5 as a hub gene within a metastasis-associated transcriptional network, with high expression predicting poor overall survival, disease-free survival, and liver metastasis risk in LUAD patients. SLC7A5 knockdown reversed epithelial-mesenchymal transition (EMT), suppressed cell migration in vitro, and significantly reduced intrapulmonary tumor growth in an orthotopic mouse model. Mechanistically, RNA-seq and metabolomic profiling revealed that SLC7A5 deficiency induced profound reprogramming of fatty acid metabolism, characterized by reduced exogenous fatty acid uptake, paradoxically enhanced fatty acid oxidation (FAO), and consequent intracellular fatty acid depletion. Palmitic acid supplementation rescued the migratory defects caused by SLC7A5 knockdown. Transcription factor enrichment analysis identified PPARA as a downstream effector, and SLC7A5 silencing significantly reduced PPARA expression, transcriptional activity, and the expression of its target genes governing fatty acid uptake, synthesis, and oxidation. CPT1 enzymatic activity was correspondingly diminished. Crucially, PPARA overexpression rescued the migratory defects induced by SLC7A5 knockdown, establishing PPARA as a critical functional mediator. Our study identifies SLC7A5 as a key regulator of LUAD metastasis through PPARA-mediated control of fatty acid metabolism, revealing an unexpected metabolic axis linking amino acid transport to lipid homeostasis. These findings establish SLC7A5 as a promising prognostic biomarker and therapeutic target for metastatic LUAD, particularly for patients at high risk of liver metastasis.

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RAD21 reshapes H3K4me3 modification to drive lung adenocarcinoma progression by activating ERK1/2 signal [ChIP-seq]

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