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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Hunter, Tony Puto, Lorena A. Brognard, John |
| Description | Author Affiliation: Puto LA ( From the Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037 and.); Brognard J ( the Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, United Kingdom.); Hunter T ( From the Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037 and hunter@salk.edu.) |
| 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 25 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-06-19 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adaptor Proteins, Signal Transducing Biosynthesis Autophagy Tumor Markers, Biological Gene Expression Regulation, Neoplastic Nuclear Proteins Prostatic Neoplasms Metabolism Repressor Proteins Tumor Suppressor Proteins Genetics Animals Cell Line, Tumor Death-Associated Protein Kinases Gene Knockdown Techniques Heterografts Intracellular Signaling Peptides And Proteins Mice Mice, Nude Neoplasm Transplantation Pancreatic Neoplasms Pathology Protein-Serine-Threonine Kinases Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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