Abstract LB-144: A p53-dependent G2/M checkpoint governed by the cell-fate factor dachshund in non-small cell lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer mortality worldwide with more than 170,000 cases diagnosed each year in the United States. Genetic studies have identified several oncogenes activated in lung cancer including K-Ras and EGFR. Tumor suppressor inactivation occurs including p53 in which LOH is observed in - 60% and mutations arise in 50%. Initially cloned as a dominant inhibitor of the hyperactive EGFR, Ellipse in Drosophila, the mammalian DACH1 gene regulates gene expression of target genes in part through interacting with DNA-binding transcription factors and in part through intrinsic DNA-sequence specific binding properties. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer. Given the importance of the EGFR in human lung cancer, we examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response. Herein, endogenous DACH1 was reduced in human non-small cell lung cancer (NSCLS). Expression levels of DACH1 correlated inversely with clinical stage and pathological grade. Re-expression of DACH1 reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated G2/M block by ectopic expression of DACH1 occurs synergistically with p53. DACH1 band p53, requiring p53 R248 and R273, residues commonly mutated in lung cancer. Fluorescent microscopy demonstrated co-localization of DACH1 with p53. Immunoprecipitation and western blot assay showed DACH1 association with p53 required the C-terminus of DACH1. DACH1 enhanced p53 transcriptional induction of p21 promoter, p53 and DACH1 repressed Rad51 expression. DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLS. Together, our studies demonstrate that p53 is DACH1 binding partner that inhibits NSCLS cellular proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-144. doi:1538-7445.AM2012-LB-144