Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy

• Published in: The Journal of biological chemistry Vol. 290; no. 25; pp. 15406 - 15420
• Main Authors: Puto, Lorena A., Brognard, John, Hunter, Tony
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.06.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - biosynthesis; Adaptor Proteins, Signal Transducing - genetics; Animals; Autophagy; Autophagy-Related Protein-1 Homolog; biomarker; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Cell Biology; cell death; Cell Line, Tumor; Co-Repressor Proteins; DAXX; 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; prostate cancer; 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 cell biology; tumor promoter; tumor suppressor gene; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; prostate cancer; DAXX; autophagy; cell death; tumor promoter; biomarker; tumor cell biology; tumor suppressor gene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.658765

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 OncomineTM 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. Transcriptional repressor DAXX suppresses several tumor suppressor genes and is up-regulated in many cancers. We demonstrate that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. In the early stages of tumorigenesis, autophagy suppresses prostate tumor formation. This is the first study to link prostate cancer development to autophagy suppression by DAXX.