title: Dachshund binds p53 to block the growth of lung adenocarcinoma cells.
abstract: Hyperactive EGF receptor (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. Reexpression of DACH1 reduced NSCLC colony formation and tumor growth in vivo via p53. Endogenous DACH1 colocalized with p53 in a nuclear, extranucleolar location, and shared occupancy of -15% of p53-bound genes in ChIP sequencing. 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.
authors.affiliation: Departments of Cancer Biology, Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,PA 19107, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Shaoxin
authors.initials: S
authors.lastname: Cai
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Andrew
authors.initials: A
authors.lastname: Quong
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Aydin
authors.initials: A
authors.lastname: Tozeren
authors.forename: Ceylan
authors.initials: C
authors.lastname: Tanes
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D045325:HCT116 Cells; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C486747:DACH1 protein, human; D005136:Eye Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C495153:RAD51 protein, human; D051135:Rad51 Recombinase