Oncotarget

Research Papers:

Acetylation of the Cell-Fate Factor Dachshund Determines p53 Binding and Signaling Modules in Breast Cancer

Ke Chen, Kongming Wu, Michael Gormley, Adam Ertel, Wei Zhang, Jie Zhou, Gabriele DiSante, Zhiping Li, Hallgeir Rui, Andrew A. Quong, Steven B. McMahon, Haiteng Deng, Michael P. Lisanti, Chenguang Wang, Richard G. Pestell _

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Oncotarget. 2013; 4:923-935. https://doi.org/10.18632/oncotarget.1094

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Abstract

Ke Chen1, Kongming Wu1, Michael Gormley1, Adam Ertel1, Jing Wang1,Wei Zhang1, Jie Zhou1, Gabriele DiSante1, Zhiping Li1, Hallgeir Rui1, Andrew A. Quong1, Steven B. McMahon1,2, Haiteng Deng3, Michael P. Lisanti2, Chenguang Wang1,2, Richard G. Pestell1,2

1 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

2 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

3 Proteomics Resource Center, Rockefeller University, New York, NY, USA

Correspondence:

Richard G. Pestell, email:

Kongming Wu, email:

Keywords: p53, breast cancer, cell fate, stem cells, dach

Received: June 13, 2013 Accepted: June 21, 2013 Published: June 21, 2013

Abstract

Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.


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