Tumor suppressors LKB1 and SMARCA4 functionally interact to regulate gene expression across diverse biological
Mohammed Bourouh1,2, Jinhong Kim1, Paola A Marignani1
1Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Introduction:
The tumor suppressor kinase liver kinase B1 (LKB1) is known to regulate the activity of the metabolic sensor AMP-activated protein kinase (AMPK), which, under energy stress, shifts metabolism from anabolism to catabolism, thus linking LKB1 to AMPK-mediated gene expression. Coupled with its role as a tumor suppressor kinase, LKB1 is an important metabolic regulator implicated in multiple malignancies and is frequently mutated in lung cancer. Previously, we discovered that LKB1 binds to the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling ATP-dependent helicase subunit SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), directly linking LKB1 to gene expression. How LKB1 and SMARCA4 collaborate to regulate gene expression in lung cancer has not been well characterized.
Methods:
We used an in silico approach to explore how LKB1 and SMARCA4 may cooperate to regulate gene expression. We analyzed our previous single-cell RNA-seq (scRNA-seq) dataset from four lung cancer cell lines with differential LKB1 and SMARCA4 expression status to identify genes regulated by both LKB1 and SMARCA4. We correlated our results using bulk RNA-seq results from human lung tumors.
Results:
We show that LKB1 and SMARCA4 likely function together to regulate gene expression in multiple biological processes in lung cancer cell lines. Gene expression profiles from LKB1- and SMARCA4-mutant cells are similar, suggesting that LKB1 and SMARCA4 function in a linear pathway to regulate gene expression. Furthermore, we observed similar results in human lung tumors, particularly in late-stage disease.
Discussion:
We propose a model where LKB1 acts as a nexus between metabolism and gene expression, acting via the SMARCA4-SWI/ SNF complex to regulate gene expression in lung cancer.
Insights
The tumor suppressor liver kinase B1 (LKB1) and SMARCA4 protein collaborate to regulate gene expression in lung cancer. This LKB1-SMARCA4 pathway is crucial for cellular metabolism and is altered in lung tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Liver kinase B1 (LKB1) is a tumor suppressor kinase regulating metabolism via AMP-activated protein kinase (AMPK).
- LKB1 is frequently mutated in lung cancer, impacting cellular metabolism and gene expression.
- LKB1 directly interacts with SMARCA4, a subunit of the SWI/SNF chromatin remodeling complex, linking it to gene regulation.
Purpose of the Study:
- To investigate the collaborative role of LKB1 and SMARCA4 in regulating gene expression in lung cancer.
- To elucidate the molecular mechanisms by which LKB1 and SMARCA4 interact to control cellular processes.
- To determine if the LKB1-SMARCA4 pathway is relevant in human lung tumors.
Main Methods:
- Utilized in silico analysis of single-cell RNA-seq (scRNA-seq) data from lung cancer cell lines with varying LKB1 and SMARCA4 expression.
- Identified genes co-regulated by LKB1 and SMARCA4.
- Correlated findings with bulk RNA-seq data from human lung tumors.
Main Results:
- LKB1 and SMARCA4 function together to regulate gene expression across multiple biological processes in lung cancer cell lines.
- Gene expression profiles in LKB1- and SMARCA4-mutant cells showed similarities, indicating a linear pathway.
- These findings were corroborated in human lung tumors, especially in advanced stages.
Conclusions:
- LKB1 acts as a critical link between cellular metabolism and gene expression in lung cancer.
- The LKB1-SMARCA4 interaction, mediated through the SMARCA4-SWI/SNF complex, is a key regulator of gene expression in lung cancer.
- This pathway represents a potential therapeutic target in lung cancer treatment.
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