| First Author | Liu X | Year | 2022 |
| Journal | Cancer Res | Volume | 82 |
| Issue | 5 | Pages | 791-804 |
| PubMed ID | 34987057 | Mgi Jnum | J:321472 |
| Mgi Id | MGI:6886115 | Doi | 10.1158/0008-5472.CAN-21-0763 |
| Citation | Liu X, et al. (2022) Chromatin remodeling induced by ARID1A loss in lung cancer promotes glycolysis and confers JQ1 vulnerability. Cancer Res |
| abstractText | ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5%-11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of 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, Pkm, and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced HIF1alpha 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 extra terminal 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. |
