Similar Datasets
Project description:Forkhead box protein A1 (FOXA1) is essential for androgen-dependent prostate cancer (PCa) growth. However, how FOXA1 levels are regulated remains elusive and its therapeutic targeting proven challenging. Here, we report FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2), which methylates FOXA1 at lysine-295. This methylation is recognized by WD40 repeat protein BUB3, which subsequently recruits ubiquitin-specific protease 7 (USP7) to remove ubiquitination and enhance FOXA1 protein stability. They functionally converge in regulating cell cycle genes and promoting PCa growth. FOXA1 is a major therapeutic target of the inhibitors of EZH2 methyltransferase activities in PCa. FOXA1-driven PCa growth can be effectively mitigated by EZH2 enzymatic inhibitors, either alone or in combination with USP7 inhibitors. Together, our study reports EZH2-catalyzed methylation as a key mechanism to FOXA1 protein stability, which may be leveraged to enhance therapeutic targeting of PCa using enzymatic EZH2 inhibitors.
| S-EPMC8026124 | biostudies-literature
Project description:FOXA1 transcription factor is essential for the development and maturation of prostate luminal epithelial cells. FOXA1 gene is frequently mutated and its expression is deregulated during prostate cancer progression. We and others have shown that FOXA1 induces androgen-dependent cell growth by transcriptional regulation of target genes related to cell cycle process, DNA replication, cell division, and apoptosis. Despite of its important roles, how FOXA1 expression itself is regulated in prostate cancer cells remains largely unknown. Here we report that EZH2 methylates one of the lysine residues (K295) on FOXA1 protein to reduce its ubiquitination and subsequent degradation. Mechanistically, this EZH2-mediated FOXA1 methylation recruits BUB3/USP7 deubiquitinase complex to remove FOXA1 ubiquitination for increased protein stability.
2021-04-15 | GSE161518 | GEO
Project description:FOXA1 transcription factor is essential for the development and maturation of prostate luminal epithelial cells. FOXA1 gene is frequently mutated and its expression is deregulated during prostate cancer progression. We and others have shown that FOXA1 induces androgen-dependent cell growth by transcriptional regulation of target genes related to cell cycle process, DNA replication, cell division, and apoptosis. Despite of its important roles, how FOXA1 expression itself is regulated in prostate cancer cells remains largely unknown. Here we report that EZH2 methylates one of the lysine residues (K295) on FOXA1 protein to reduce its ubiquitination and subsequent degradation. Mechanistically, this EZH2-mediated FOXA1 methylation recruits BUB3/USP7 deubiquitinase complex to remove FOXA1 ubiquitination for increased protein stability.
2021-04-15 | GSE161517 | GEO
Project description:Regulation of FOXA1 protein stability by Polycomb and BUB3/USP7 deubiquitin complexes in prostate cancer
| PRJNA678634 | ENA
Project description:Regulation of FOXA1 protein stability by Polycomb and BUB3/USP7 deubiquitin complexes in prostate cancer [RNA-Seq]
| PRJNA678636 | ENA
Project description:Regulation of FOXA1 protein stability by Polycomb and BUB3/USP7 deubiquitin complexes in prostate cancer [ChIP-Seq]
| PRJNA678635 | ENA
Project description:USP7 (Ubiquitin Specific processing Protease-7) is a deubiquitinase which, over the past decade emerged as a critical regulator of cellular processes. Deregulation of USP7 activity has been linked to cancer, making USP7 inhibition an appealing anti-cancer strategy. The identification of novel USP7 substrates and additional USP7-dependent cellular activities will broaden our knowledge towards potential clinical application of USP7 inhibitors. Results presented in this study uncover a novel and pivotal function of USP7 in the maintenance of genomic stability. Upon USP7 depletion we observed prolonged mitosis and mitotic abnormalities including micronuclei accumulation, lagging chromosomes and karyotype instability. Inhibition of USP7 with small molecule inhibitors stabilizes cyclin B and causes mitotic abnormalities. Our results suggest that these USP7-dependent effects are mediated by decreased levels of spindle assembly checkpoint (SAC) component Bub3, which we characterized as an interacting partner and substrate of USP7. In silico analysis across the NCI-60 panels of cell lines supports our results where lower levels of USP7 strongly correlate with genomic instability. In conclusion, we identified a novel role of USP7 as regulator of the SAC component Bub3 and genomic stability.
| S-EPMC4116516 | biostudies-literature
Project description:MicroRNAs are a class of small non-coding regulatory RNA molecules that regulate mRNAs post-transcriptionally. Recent evidence has shown that miRNAs target entire functionally related proteins such as protein complexes and biological pathways. However, characterizing the influence of miRNAs on genes whose encoded proteins are part of protein complexes has not been studied in the context of disease. We propose an entropy-based framework to identify miRNA-mediated dysregulation of functionally related proteins during prostate cancer progression. The proposed framework uses experimentally verified miRNA-target interactions, functionally related proteins and expression data to identify miRNA-influenced protein complexes in prostate cancer, and identify genes that are dysregulated as a result. The framework constructs correlation matrixes between functionally related proteins and miRNAs that have targets in the complex, and assesses the changes in the Shannon entropy of the modules across different stages of prostate cancer. Results reveal that SMAD4 and HDAC containing protein complexes are highly affected and disrupted by miRNAs, particularly miRNA-1 and miRNA-16. Using biological pathways to define functionally related proteins reveals that NF-kB-, RAS-, and Syndecan-mediated pathways are dysregulated due to miRNA-1- and miRNA-16-mediated regulation. These results suggest that miRNA-1 and miRNA-16 are important master regulators of miRNA-mediated regulation in prostate cancer. Moreover, results reveal that miRNAs with high-influence on the disrupted protein complexes are diagnostic and prognostic biomarker candidates for prostate cancer progression. The observation of miRNA-mediated protein complex regulation and miRNA-mediated pathway regulation, with partial experimental verification from previous studies, demonstrates that our framework is a promising approach for the identification of novel miRNAs and protein complexes related to disease progression.
| S-EPMC3877262 | biostudies-literature
Project description:Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data have uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.
| S-EPMC3157014 | biostudies-literature
Project description:FOXA1 (also known as hepatocyte nuclear factor 3α, or HNF-3α) is a protein of the FKHD family transcription factors. FOXA1 has been termed as a pioneer transcription factor due to its unique ability of chromatin remodeling in which the chromatin can be decompacted to allow genomic access by nuclear hormone receptors, including androgen receptor (AR) and estrogen receptor (ER). In this review, we discuss our current understanding of FOXA1 regulation of prostatic and non-prostatic AR-chromatin targeting. We present an updated model wherein FOXA1:AR equilibrium in the nuclei defines prostatic AR binding profile, which is perturbed in prostate cancer with FOXA1 and/or AR de-regulation. Finally, we discuss recent efforts in exploring new horizons of AR-independent functions of FOXA1 in prostate cancer and interesting directions to pursue in future studies.
| S-EPMC4477823 | biostudies-literature