Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy

J Biol Chem. 2015 Jun 19;290(25):15406-15420. doi: 10.1074/jbc.M115.658765. Epub 2015 Apr 22.

Abstract

The DAXX transcriptional repressor was originally associated with apoptotic cell death. However, recent evidence that DAXX represses several tumor suppressor genes, including the DAPK1 and DAPK3 protein kinases, and is up-regulated in many cancers argues that a pro-survival role may predominate in a cancer context. Here, we report that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. Through stable gene knockdown and mouse subcutaneous xenograft studies, we demonstrate that DAXX promotes tumorigenicity of human ALVA-31 and PC3 prostate cancer (PCa) cells in vivo. Importantly, DAXX represses expression of essential autophagy modulators DAPK3 and ULK1 in vivo, revealing autophagy suppression as a mechanism through which DAXX promotes PCa tumorigenicity. Furthermore, DAXX knockdown increases autophagic flux in cultured PCa cells. Finally, interrogation of the Oncomine(TM) database suggests that DAXX overexpression is associated with malignant transformation in several human cancers, including prostate and pancreatic cancers. Thus, DAXX may represent a new cancer biomarker for the detection of aggressive disease, whose tissue-specific down-regulation can serve as an improved therapeutic modality. Our results establish DAXX as a pro-survival protein in PCa and reveal that, in the early stages of tumorigenesis, autophagy suppresses prostate tumor formation.

Keywords: DAXX; autophagy; biomarker; cell death; prostate cancer; tumor cell biology; tumor promoter; tumor suppressor gene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Autophagy*
  • Autophagy-Related Protein-1 Homolog
  • Biomarkers, Tumor / biosynthesis*
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Co-Repressor Proteins
  • Death-Associated Protein Kinases / genetics
  • Death-Associated Protein Kinases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Molecular Chaperones
  • Neoplasm Transplantation
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / genetics
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Co-Repressor Proteins
  • DAXX protein, human
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • Autophagy-Related Protein-1 Homolog
  • DAPK3 protein, human
  • Death-Associated Protein Kinases
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human