Tumor suppressors LKB1 and SMARCA4 functionally interact to regulate gene expression across diverse biological processes in lung cancer

TL;DR

This study explores how two tumor suppressor proteins, LKB1 and SMARCA4, work together to control gene activity in lung cancer cells and tumors.

Contribution

The study reveals a functional interaction between LKB1 and SMARCA4 in regulating gene expression in lung cancer.

Findings

LKB1 and SMARCA4 regulate gene expression in multiple biological processes in lung cancer cell lines.

Mutant LKB1 and SMARCA4 cells show similar gene expression profiles, suggesting they function in a linear pathway.

Findings in cell lines are mirrored in late-stage human lung tumors.

Abstract

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.

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.

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.

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.

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