The role of SMARCA4 in lung cancer

Abstract

Lung cancer remains one of the leading causes of mortality among cancer patients. Chromatin remodeling is a crucial epigenetic process in cancer, primarily regulated by alterations in genes encoding subunits of the switch/sucrose non-fermentable (SWI/SNF) complex. SMARCA4 and SMARCA2 are two mutually exclusive catalytic subunits within the SWI/SNF complex responsible for utilizing ATP hydrolysis to provide energy for chromatin remodeling. In lung cancer, SMARCA4 is one of the most common mutated subunits of the SWI/SNF complex. Patients with SMARCA4-deficient lung cancer typically experience poorer clinical outcomes. At present, there is no established targeted therapy designed specifically for this type of cancer. Here, we mainly discuss the mechanisms of SMARCA4 in lung cancer development and progression, its co-mutations and mutually exclusive mutations, cellular origin, clinical pathological characteristics, diagnosis and treatment of SMARCA4-deficient lung cancer. We also investigate the concept of synthetic lethality between SMARCA4 and SMARCA2, along with susceptibility to SMARCA4-deficient lung cancer and potential applications of immunotherapy.

Fig. 1

Based on the subunits composition and arrangement, the SWI/SNF complexes could be categorized into three types: BAF, PBAF and ncBAF, with highly conserved core subunits such as SMARCB1, SMARCA4, SMARCC1 and SMARCC2.

Fig. 2

Structural homology and mutation profiles of SMARCA4 and SMARCA2 in lung cancer. The protein domain architectures of SMARCA4 and SMARCA2 exhibit high structural homology, sharing six conserved functional domains. SMARCA4 exhibits frequent and widespread somatic mutations across multiple domains, with hotspot alterations particularly concentrated in its ATPase domain. In contrast, SMARCA2 is nearly mutation-free in lung cancer.

Fig. 3

SMARCA4 and SMARCA2 Structural and Functional Domains. SMARCA4 and SMARCA2 are core subunits of the SWI/SNF chromatin remodeling complex and share six highly conserved domains (PRR domain, OLQ domain, HSA domain, ATPase domain, RB-binding domain and bromo domain), each playing distinct roles in chromatin remodeling, protein interactions, and transcriptional regulation. The proline-rich domain (4-344 in SMARCA4) plays a crucial role in p53 destabilization by mediating interaction between histone acetyltransferase protein CBP and p53. This interaction promotes p53 ubiquitination and degradation. The QLQ domain (171-206 in SMARCA4) is involved in protein-protein interactions within the SWI/SNF complex and with other regulatory proteins. The HSA domain could regulate the activity of chromatin-remodeling ATPase. The HSA domain (475-532 in SMARCA4) could interact with actin, BCL7, Ku70 and BAF250a/ARID1A, linking the SWI/SNF complex to cytoskeletal organization, DNA repair and chromatin remodeling processes. The ATPase domain (774-1237 in SMARCA4) is the catalytic core of SMARCA4/2, providing the energy required for chromatin remodeling through ATP hydrolysis. This domain enables the SWI/SNF complex to slide, eject nucleosomes, thereby regulating access to DNA for transcription factors and other DNA-binding proteins. The RB-binding domain (LxCxE motif in SMARCA4) forms complexes with RB proteins which are key regulators of the cell cycle. This interaction facilitates the formation of complexes that induce cell cycle arrest. The Bromodomain (1455-1521 in SMARCA4) is a conserved structural motif that interacts with acetylated histones. This interaction targets the SWI/SNF complex to regions of active transcription.

Fig. 4

Differences between wild-type and SMARCA4 mutant lung cancers and their therapeutic opportunities. a. SMARCA4 deletion induces replication stress and ATR dependency: SMARCA4 deletion promotes replication stress, activating the ATR-mediated DNA damage response to stabilize replication forks. ATR inhibition disrupts fork progression, leading to fork collapse, DNA damage and cell death, sensitizing the SMARCA4 mutant lung cancer cells to ATR inhibitors. b. Metabolic reprogramming in SMARCA4/2 deficient cells: SMARCA4/2 drives a metabolic shift, utilizing glutamine over glucose as the primary carbon source to fuel the tricarboxylic acid cycle and OXPHOS, supporting cell survival and proliferation. c. Cell cycle dysregulation and CDK4/6 inhibitor sensitivity: SMARCA4/2 loss in lung cancers reduces cyclin D1 expression through the CCND1 chromatin accessibility restriction and the activity suppression of c-Jun, impairing G1-to-S phase progression and increasing the sensitivity of CDK4/6 inhibitors.