Dachshund Binds p53 to Block the Growth of Lung Adenocarcinoma Cells

Abstract

Hyperactive EGFR and mutant p53 are common genetic abnormalities driving the progression of non-small cell lung cancer (NSCLC), the leading cause of cancer deaths in the world. The Drosophila gene Dachshund (Dac) was originally cloned as an inhibitor of hyperactive EGFR alleles. Given the importance of EGFR signaling in lung cancer etiology, we examined the role of DACH1 expression in lung cancer development. DACH1 protein and mRNA expression was reduced in human NSCLC. Re-expression of DACH1 reduced NSCLC colony formation and tumor growth in vivo via p53. Endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar location, and shared occupancy of -15% of p53 bound genes in ChIP Seq. The C-terminus of DACH1 was necessary for direct p53 binding, contributing to the inhibition of colony formation and cell cycle arrest. Expression of the stem cell factor SOX2 was repressed by DACH1, and SOX2 expression was inversely correlated with DACH1 in NSCLC. We conclude that DACH1 binds p53 to inhibit NSCLC cellular growth.

DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling

“…As previously reported, DACH1 was highly expressed in the nuclei of lung epithelial cells [10], but dramatically reduced in adenocarcinoma, squamous carcinoma, and large cell carcinoma (Fig. 1A, B).…”

“…In this respect, transgenic model demonstrates that Six1 and Eya are required for maintaining epithelial progenitor cell, regulating epithelial branching, mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis [3,4]. Recently, more evidence indicates RDGN network is implicated in the development of human cancer, including breast and lung carcinoma [5-10]. Functional studies have identified DACH1 as a negative regulator of TGF-β and Wnt signaling to repress cancer cell migration and invasion [11,12].…”

“…DACH1 inhibits EMT and tumor initiated cells in breast cancer and glioma [19-21]. DACH1 can directly associate with p53 and enhance its function in breast and lung cancer [10,22]. Inactivation of DACH1 in human cancer tissues was observed by mechanisms of gene deletion, mutation, or promoter hypermethylation [21,23].…”

“…In contrast, DACH1 expression was reduced in human NSCLC. Reexpression of DACH1 reduced colony formation and tumor growth in NSCLC cell lines via synergistic action with p53 [10]. However, the mechanism by which DACH1 regulates lung cancer growth is not fully understood.…”

Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

“…In vitro protein-protein interactions were performed as described previously (24,25). In vitro translated proteins were prepared by coupled transcription-translation with a TNT-coupled reticulocyte lysate kit (Promega) using plasmid DNA (1.0 mg) in a total of 50 mL.…”