Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis

Abstract

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-_ 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, miR- 22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF-_ 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.