Chromatin Remodeling Induced by ARID1A Loss in Lung Cancer Promotes Glycolysis and Confers JQ1 Vulnerability
Xiaoyu Liu1,2, Zhi Li3,4, Zhongmin Wang2,5
1Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Bengbu Medical College, Anhui, China.
Abstract:
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:
This study links ARID1A loss with enhanced glycolysis in lung cancer and demonstrates the preclinical efficacy of BET inhibitor therapy as a strategy to combat tumor growth.
Insights
Loss of ARID1A in lung cancer promotes tumor growth by enhancing glycolysis. Targeting glycolysis or using BET inhibitors shows promise for treating ARID1A-deficient lung adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- ARID1A is a crucial subunit of the mammalian SWI/SNF complex, frequently mutated in lung cancers.
- The precise role of ARID1A loss in lung cancer initiation and progression is not fully understood.
- Dysregulation of SWI/SNF complexes is implicated in various cancers, highlighting the need to define ARID1A's specific functions.
Purpose of the Study:
- To investigate the impact of ARID1A loss on lung cancer development.
- To elucidate the molecular mechanisms driving tumorigenesis in the absence of ARID1A.
- To identify potential therapeutic vulnerabilities associated with ARID1A deficiency in lung cancer.
Main Methods:
- Utilized genetically engineered mouse models (KP and KPA) for lung cancer studies.
- Performed transcriptome profiling to analyze gene expression changes.
- Conducted chromatin immunoprecipitation and metabolic analyses.
- Assessed the efficacy of glycolysis inhibition and BET inhibitor (JQ1) treatment.
Main Results:
- ARID1A loss promoted lung tumorigenesis and enhanced glycolysis.
- ARID1A deficiency led to increased expression of glycolytic regulators (Pgam1, Pkm, Pgk1) via HIF1α and BRD4.
- Inhibition of glycolysis or BET signaling suppressed ARID1A-deficient lung tumor growth.
- ARID1A loss correlated negatively with glycolysis-related genes in human lung adenocarcinoma.
Conclusions:
- ARID1A loss drives lung cancer progression through metabolic reprogramming, specifically enhancing glycolysis.
- Targeting glycolysis or utilizing BET inhibitors represents a viable therapeutic strategy for ARID1A-deficient lung cancers.
- This study reveals a critical link between ARID1A status, metabolic alterations, and therapeutic response in lung adenocarcinoma.
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