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 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.

PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma

“…Notably, great importance has been attached to the implication of PHF8 in transcriptional activating the expression of EMT-related markers, SNAI1 and VIM, and attenuating E-cadherin level [16, 17]. However, it is unclear how PHF8 downregulates E-cadherin expression.…”

Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

“…However, a compensatory mechanism that upregulates their expression under hypoxia can maintain, even enhance their functions [15]. The histone demethylase PHF8 contributes to oncogenesis by promoting epithelial to mesenchymal transition (EMT) [23] and cell-cycle progression [17,23,38], and inhibiting apoptosis [26,39]. This study identifies a novel regulatory role for PHF8 during hypoxia, showing that it acts through HIF1α and H3K4me3, shedding light on novel functions of PHF8 in cancer biology.…”

“…Chromatin immunoprecipitation (ChIP) followed by PCR was performed as previously described [19,23]. Briefly, cells were fixed with methanol-free 1% formaldehyde (Thermo Fisher), quenched with 0.125 M glycine, and then lysed with ChIP lysis buffer (50 mM HEPES, pH 7.9, 140 mM NaCl, 1 mM EDTA, 10% Glycerol, 0.5% NP-40, 0.25% Triton-X 100).…”

Synergistic interplay between PHF8 and HER2 signaling contributes to breast cancer development and drug resistance

“…Intriguingly, PHF8 mRNA levels are only slightly elevated across breast cancers (n=1085) as well as in subtypes of breast cancers, compared with normal tissue (n=291) (Supplemental Figure 1A and B). As PHF8 is subject to both post-transcriptional and posttranslational regulations such as c-MYC-miR-22-PHF8 (Maina et al, 2016;Shao et al, 2017) and USP7-PHF8 (Wang et al, 2016) regulatory mechanisms, the actual PHF8 protein levels in cancers can differ from its mRNA levels. We increased our breast cancer samples from previous study to a pool of samples of 486 breast cancer, 20 normal breast tissues, and 50 metastatic lymph nodes (US BIOMAX).…”

“…Beyond overexpression, the post-transcriptional and posttranslational regulations of PHF8 were also recently elucidated. We identified the c-MYC-miR-22-PHF8 regulatory axis, through which the elevated c-MYC can indirectly upregulates PHF8 by represses miR-22, a microRNA that targets and represses PHF8 (Maina et al, 2016;Shao et al, 2017). Moreover, USP7-PHF8 positive feedback loop was discovered, i.e.…”