期刊
NUCLEIC ACIDS RESEARCH
卷 45, 期 4, 页码 1687-1702出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw1093
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资金
- Department of Anatomy and Cell Biology
- Carver College of Medicine
- University of Iowa
- Carver Trust Young Investigator Award from Roy J. Carver Charitable Trust [01-224]
- The National Institutes of Health
- CTSA through ICTS (Institute for Clinical and Translational Science) at University of Iowa [UL1RR024979]
- ACSIRG seed grant [IRG-77-004-34]
- American Cancer Society
- administrated through Holden Comprehensive Cancer Center at University of Iowa
- Breast Cancer Research Award
- Holden Comprehensive Cancer Center at the University of Iowa
- National Institutes of Health grant [P30 CA86862]
- Libraries and Provost's Open Access Fund at University of Iowa
Histone demethylase PHF8 is upregulated and plays oncogenic roles in various cancers; however, the mechanisms underlying its dysregulation and functions in carcinogenesis remain obscure. Here, we report the novel functions of PHF8 in EMT ( epithelial to mesenchymal transition) and breast cancer development. Genome-wide gene expression analysis revealed that PHF8 overexpression induces an EMTlike process, including the upregulation of SNAI1 and ZEB1. PHF8 demethylates H3K9me1, H3K9me2 and sustains H3K4me3 to prime the transcriptional activation of SNAI1 by TGF- beta signaling. We show that PHF8 is upregulated and positively correlated with MYC at protein levels in breast cancer. MYC posttranscriptionally regulates the expression of PHF8 via the repression of microRNAs. Specifically, miR22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF- beta signaling. This novel MYC/microRNAs/PHF8 regulatory axis thus places PHF8 as an important downstream effector of MYC. Indeed, PHF8 contributes to MYC-induced cell proliferation and the expression of EMT-related genes. We also report that PHF8 plays important roles in breast cancer cell migration and tumor growth. These oncogenic functions of PHF8 in breast cancer confer its candidacy as a promising therapeutic target for this disease.
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