ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5% to 11% of
lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of the switch/
sucrose non-fermentable (SWI/SNF) complexes in
cancers, the significance of ARID1A loss and its implications in
lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of
lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung
tumorigenesis. Analysis of the transcriptome profiles of KP and KPA
tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1,
pyruvate kinase M (Pkm), and Pgk1 was significantly increased in ARID1A-deficient lung
tumors. Furthermore, ARID1A loss increased
chromatin accessibility and enhanced
hypoxia-inducible factor-1α (HIF1α) binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in
lung adenocarcinoma also resulted in loss of
histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone-4
lysine at the promoters of Pgam1, Pkm, and Pgk1, and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient
tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung
tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extraterminal
protein (
BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient
lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human
lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports
tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient
lung cancer.
SIGNIFICANCE: