Title: Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma.
Authors: Walter, David M; Venancio, Olivia S; Buza, Elizabeth L; Tobias, John W; Deshpande, Charuhas; Gudiel, A Andrea; Kim-Kiselak, Caroline; Cicchini, Michelle; Yates, Travis J; Feldser, David M
Published In Cancer Res, (2017 04 01)
Abstract: Chromatin-modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood. Using a CRISPR-based approach, we systematically inactivated three of the most commonly mutated chromatin regulatory genes in two KrasG12D-driven mouse models of lung adenocarcinoma to characterize the impact of their loss. Targeted inactivation of SWI/SNF nucleosome-remodeling complex members Smarca4 (Brg1) or Arid1a had complex effects on lung adenocarcinoma initiation and progression. Loss of either Brg1 or Arid1a were selected against in early-stage tumors, but Brg1 loss continued to limit disease progression over time, whereas loss of Arid1a eventually promoted development of higher grade lesions. In contrast to these stage-specific effects, loss of the histone methyltransferase Setd2 had robust tumor-promoting consequences. Despite disparate impacts of Setd2 and Arid1a loss on tumor development, each resulted in a gene expression profile with significant overlap. Setd2 inactivation and subsequent loss of H3K36me3 led to the swift expansion and accelerated progression of both early- and late-stage tumors. However, Setd2 loss per se was insufficient to overcome a p53-regulated barrier to malignant progression, nor establish the prometastatic cellular states that stochastically evolve during lung adenocarcinoma progression. Our study uncovers differential and context-dependent effects of SWI/SNF complex member loss, identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma, and establishes model systems to facilitate further study of chromatin deregulation in lung cancer. Cancer Res; 77(7); 1719-29. ©2017 AACR.
PubMed ID: 28202515
MeSH Terms: Adenocarcinoma of Lung; Adenocarcinoma/etiology; Adenocarcinoma/prevention & control*; Animals; Chromatin/physiology*; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Helicases/physiology; DNA-Binding Proteins; HEK293 Cells; Histone-Lysine N-Methyltransferase/physiology*; Humans; Lung Neoplasms/etiology; Lung Neoplasms/prevention & control*; Mice; Mice, Inbred C57BL; Mutation; Nuclear Proteins/physiology; Proto-Oncogene Proteins p21(ras)/genetics; Transcription Factors/physiology; Tumor Suppressor Protein p53/physiology; Tumor Suppressor Proteins/physiology*