Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer.

Ke Chen, Kongming Wu, Michael Gormley, Adam Ertel, Jing Wang, 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

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)923-935
    Number of pages12
    JournalOncotarget
    Volume4
    Issue number6
    Publication statusPublished - Jun 2013

    Keywords

    • Breast cancer
    • Cell fate
    • Dach
    • P53
    • Stem cells

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