期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 25, 页码 15406-15420出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.658765
关键词
autophagy; biomarker; cell death; prostate cancer; tumor cell biology; tumor promoter; tumor suppressor gene; DAXX
资金
- National Institutes of Health, NCI [CA14195, CA082683, 5T32CA009523-28]
- Department of Defense [DoD-W81XWH-08-1-0209]
- Cancer Research UK Manchester Institute
- Cancer Research UK [12936] Funding Source: researchfish
Background: Transcriptional repressor DAXX suppresses several tumor suppressor genes and is up-regulated in many cancers. Results: We demonstrate that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. Conclusion: In the early stages of tumorigenesis, autophagy suppresses prostate tumor formation. Significance: This is the first study to link prostate cancer development to autophagy suppression by DAXX. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据