Role of the DREAM complex in the lung tumor suppression

点击翻译按钮获取中文摘要

ABSTRACT Lung cancer is the major cause of cancer deaths in the U.S. and worldwide. The most common types of lung cancer are non-small cell lung carcinoma (NSCLC, 84%) and small cell lung carcinoma (SCLC, 13%). NSCLC includes two major histological subtypes, adenocarcinoma (AC), and squamous cell carcinoma (SCC). All subtypes of lung cancer are thought to arise from airway epithelial cells damaged by genotoxic exposure, which most commonly include tobacco smoke and radon radiation. These damaged cells frequently acquire early driver mutations in the KRAS gene that could be also present in advanced lung cancers. However, even in the cases with significant and chronic exposure (such as in heavy smokers), not all damaged cells give rise to cancer, and the mechanisms that prevent the progression of early premalignant lesions to cancer are still not fully understood. Studies using genetically engineered mouse models (GEMMs) highlighted the roles of cell cycle arrest and senescence, mediated by retinoblastoma (Rb) family proteins and p53, in protection from lung tumorigenesis. However, further research is required to better understand the barriers to lung carcinogenesis at the molecular level, and to develop accurate models representing early stages of lung cancer pathogenesis. Previously, we characterized a transcriptional repressor complex called DREAM that assembles in G0/G1 when Rb-like protein p130 recruits E2F4, DP1, and a stable core of five proteins including LIN9, LIN37, LIN52, LIN54, and RBBP4. The DREAM binds to promoters and mediates the repression of >800 cell cycle genes, including most genes required for DNA damage response and repair. Phosphorylation of serine-28 residue in LIN52 by DYRK1A kinase is required for the DREAM assembly. DREAM-DYRK1A pathway could be relevant to cancer because either inhibition of DYRK1A, or S28A-LIN52 mutation result in bypass of the oncogenic Ras- induced senescence in the immortalized human and mouse cell lines. The KRAS gene is mutated in 15% - 30% of NSCLC cases, and its driver role in lung cancer is strongly supported by encouraging NSCLC clinical data using KRASG12C-targeted therapeutics. However, the pathophysiological significance of the DREAM disruption in lung cancer is not known, and the mechanisms of senescence bypass in the cells lacking DREAM are not well understood. Here, we test our hypothesis that DREAM complex contributes to tumor prevention by suppressing DNA repair in the damaged cells during early stages of lung cancer pathogenesis. Previously, the role of DREAM in lung cancer could not be directly investigated due to a lack of suitable mouse models. To address this knowledge gap, we generated a DREAM-less mouse homozygous for S28A mutation in the Lin52 gene, using CRISPR-Cas9 gene editing. We will use our novel Lin52S28A mouse model to investigate the role of the DYRK1A-DREAM pathway during the early steps of lung cancer pathogenesis driven by genotoxic stress or KrasG12C mutation.