Similar Datasets
Project description:The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified PHF8, a histone demethylase of the Jumonji C protein family, as a novel pro-metastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not sub-cutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.
2022-02-23 | GSE196897 | GEO
Project description:The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified PHF8, a histone demethylase of the Jumonji C protein family, as a novel pro-metastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not sub-cutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.
2022-02-23 | GSE196905 | GEO
Project description:The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis
| PRJNA807688 | ENA
Project description:Histone demethylase plant homeodomain (PHD) finger protein 8 (PHF8) has been implicated in tumor development and malignant progression in various types of cancers. However, its potential roles in gastric cancer (GC) have not been explored. In this report, we show that PHF8 expression is upregulated in GC tissues, and the enhanced PHF8 level indicates a poor prognosis of GC patients. PHF8 knockdown reduces proliferation and metastasis of GC cells, while PHF8 overexpression has the opposite effects. Mechanistically, PHF8 interacts with β-catenin, and binds to the promoter region of vimentin, leading to the promotion of vimentin transcription. In addition, we show that H. pylori, the single most important risk factor for GC, markedly induce PHF8 expression. Our results suggest that H. pylori-induced PHF8-β-catenin-vimentin axis activation is a novel mechanism for GC malignant progression. Thus, we identify PHF8 as an oncogenic factor of GC, and suggest PHF8 might be a potential molecular target for therapeutic approaches for GC.
| S-EPMC5385635 | biostudies-literature
Project description:The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis [ChIP-seq]
| PRJNA807678 | ENA
Project description:The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis [RNA-seq]
| PRJNA807691 | ENA
Project description:Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.
| S-EPMC5776039 | biostudies-literature
Project description:The histone demethylase PHF8 has been implicated in multiple pathological disorders, including X-linked mental retardation and tumorigenesis. However, it is not clear how the abundance and function of PHF8 are regulated. Here, we report that PHF8 physically associates with the deubiquitinase USP7. Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation. The USP7-encoding gene was also transcriptionally regulated by PHF8, via positive feedback. USP7 was overexpressed in breast carcinomas, and the level of expression positively correlated with expression of PHF8 and cyclin A2 and with the histological grade of breast cancer. We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage. Moreover, USP7-promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair. Our study mechanistically links USP7 to epigenetic regulation and DNA repair. Moreover, these data support the pursuit of USP7 and PHF8 as potential targets for breast cancer intervention, especially in combination with chemo- or radiotherapies.
| S-EPMC4887182 | biostudies-literature
Project description: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.
| S-EPMC5389682 | biostudies-literature
Project description:X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of approximately 7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.
| S-EPMC3072215 | biostudies-literature