Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis

• Published in: Nucleic acids research 2017-02, Vol.45 (4), p.1687-1702
• Main Authors: Shao, Peng, Liu, Qi, Maina, Peterson Kariuki, Cui, Jiayue, Bair, Thomas B, Li, Tiandao, Umesalma, Shaikamjad, Zhang, Weizhou, Qi, Hank Heng
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Gene regulation, Chromatin and Epigenetics; Heterografts; Histone Demethylases - metabolism; Histones - metabolism; Humans; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; Transcription Factors - metabolism; Transcriptional Activation; Transforming Growth Factor beta - pharmacology
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkw1093

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 EMT-like process, including the upregulation of SNAI1 and ZEB1. PHF8 demethylates H3K9me1, H3K9me2 and sustains H3K4me3 to prime the transcriptional activation of SNAI1 by TGF-β signaling. We show that PHF8 is upregulated and positively correlated with MYC at protein levels in breast cancer. MYC post-transcriptionally regulates the expression of PHF8 via the repression of microRNAs. Specifically, miR-22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF-β 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.