scholarly journals EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marita Zoma ◽  
Laura Curti ◽  
Dheeraj Shinde ◽  
Domenico Albino ◽  
Abhishek Mitra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Target Genes ◽  
Genetically Engineered ◽  
Post Translational Modification ◽  
Pten Loss ◽  
Genetically Engineered Mouse Model ◽  
Oncogenic Activity ◽  
Domain Interactions ◽  
Prostate Cancers

AbstractThe TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Ptenflox/floxRosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.

scholarly journals A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

2019 ◽  
Vol 116 (48) ◽  
pp. 24184-24195 ◽  
Author(s):  
Iacovos P. Michael ◽  
Sadegh Saghafinia ◽  
Douglas Hanahan
Keyword(s):  
Tumor Growth ◽  
Target Genes ◽  
Genetically Engineered ◽  
Malignant Progression ◽  
Metastasis Suppressor ◽  
Invasion And Metastasis ◽  
Biologically Relevant ◽  
Genetically Engineered Mouse Model ◽  
Functional Involvement

MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robo2 and P2ry1, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs—miRNA-130/301—that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.

scholarly journals The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

2019 ◽  
Vol 218 (6) ◽  
pp. 1943-1957 ◽  
Author(s):  
Dawid G. Nowak ◽  
Ksenya Cohen Katsenelson ◽  
Kaitlin E. Watrud ◽  
Muhan Chen ◽  
Grinu Mathew ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Genetically Engineered ◽  
Phosphatase Inhibitors ◽  
Genetically Engineered Mouse Model ◽  
Key Driver ◽  
The Common ◽  
Chromosome 16Q ◽  
Mutant Cells

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill PTEN mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.

scholarly journals ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zineb Mounir ◽  
Joshua M Korn ◽  
Thomas Westerling ◽  
Fallon Lin ◽  
Christina A Kirby ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Methylation Site ◽  
Prostate Cancer Cells ◽  
Arginine Methyltransferase ◽  
Inhibitory Function ◽  
Lineage Differentiation ◽  
Prostate Cancers ◽  
Prostate Epithelium

The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR’s ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.

scholarly journals Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma

2021 ◽  
Author(s):  
Shawn M Davidson ◽  
Julia E. Heyman ◽  
James P O'Brien ◽  
Amy C. Liu ◽  
Daniel R. Schmidt ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Pyruvate Kinase ◽  
Normal Prostate ◽  
Pten Loss ◽  
Conditional Allele ◽  
Normal Prostate Tissue ◽  
Splice Isoform ◽  
Isoform Expression ◽  
Prostate Cancers

Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2). This isoform can promote anabolic metabolism to support cell proliferation; however, Pkm2 expression is dispensable for many cancers in vivo. Pyruvate kinase M1 (Pkm1) isoform expression is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied. Pkm1 is expressed in normal prostate tissue; thus, to test how differential pyruvate kinase isoform expression affects cancer initiation and progression we generated mice harboring a conditional allele of Pkm1 and crossed this allele, as well as a Pkm2 conditional allele, to a Pten loss-driven prostate cancer model. We found that Pkm1 loss leads to Pkm2 expression and accelerates prostate cancer, while deletion of Pkm2 leads to increased Pkm1 expression and suppresses cancer. Consistent with these data, a small molecule pyruvate kinase activator that mimics a PKM1-like state suppresses progression of established prostate tumors. PKM2 expression is retained in most human prostate cancers, arguing that pharmacological PKM2 activation may be beneficial for some prostate cancer patients.

scholarly journals PAQR6 Upregulation Is Associated with AR Signaling and Unfavorite Prognosis in Prostate Cancers

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1383
Author(s):  
Min Yang ◽  
Jean Chong Li ◽  
Chang Tao ◽  
Sa Wu ◽  
Bin Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Progesterone Receptor ◽  
Disease Progression ◽  
Expression Profiles ◽  
Cell Types ◽  
Survival Outcomes ◽  
Primary Cancer ◽  
Prostate Cancers ◽  
Cancer Tissues

Progesterone-induced rapid non-genomic signaling events have been confirmed through several membrane progesterone receptors (mPR). Some mPRs were reported to correlate with cancer progression and patient prognosis. In this study, we conducted a comprehensive analysis of all progesterone receptor (PGR)-related genes in prostate cancer tissues and examined the correlations of their expression levels with disease progression and patient survival outcomes. We utilized multiple RNA-seq and cDNA microarray datasets to analyze gene expression profiles and performed logistics aggression and Kaplan-Meier survival analysis after stratifying patients based on tumor stages and Gleason scores. We also used NCBI GEO datasets to examine gene expression patterns in individual cell types of the prostate gland and to determine the androgen-induced alteration of gene expression. Spearman coefficient analysis was conducted to access the correlation of target gene expression with treatment responses and disease progression status. The classic PGR was mainly expressed in stromal cells and progestin and adipoQ receptor (PAQR) genes were the predominant genes in prostate epithelial cells. Progesterone receptor membrane component-1 (PGRMC1) was significantly higher than PGRMC2 in all prostate cell types. In prostate cancer tissues, PAQR6 expression was significantly upregulated, while all other genes were largely downregulated compared to normal prostate tissues. Although both PAQR6 upregulation and PAQR5 downregulation were significantly correlated with tumor pathological stages, only PAQR6 upregulation was associated with Gleason score, free-prostate-specific antigen (fPSA)/total-PSA (tPSA) ratio, and patient overall survival outcomes. In addition, PAQR6 upregulation and PGR/PGRMC1 downregulation were significantly associated with a quick relapse. Conversely, in neuroendocrinal prostate cancer (NEPC) tissues, PAQR6 expression was significantly lower, but PAQR7/8 expression was higher than castration-resistant prostate cancer (CRPC) tissues. PAQR8 expression was positively correlated with androgen receptor (AR) score and AR-V7 expression levels but inversely correlated with NEPC score in metastatic CRPC tumors. This study provides detailed expression profiles of membrane progesterone receptor genes in primary cancer, CRPC, and NEPC tissues. PAQR6 upregulation in primary cancer tissues is a novel prognostic biomarker for disease progression, overall, and progression-free survival in prostate cancers. PAQR8 expression in CRPC tissues is a biomarker for AR activation.

scholarly journals Cyclocreatine suppresses prostate tumorigenesis through dual effects on SAM and creatine metabolism

2021 ◽  
Author(s):  
Rachana Patel ◽  
Lisa Rodgers ◽  
Catriona A. Ford ◽  
Linda K Rushworth ◽  
Janis Fleming ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
De Novo ◽  
Basal Respiration ◽  
Genetically Engineered ◽  
Prostate Tumorigenesis ◽  
Genetically Engineered Mouse Model ◽  
Creatine Metabolism

ABSTRACTProstate cancer is highly prevalent, being the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of PTEN and SPRY2 (Sprouty 2) tumour suppressors, we identified enhanced creatine metabolism within the phosphagen system in progressive disease. Altered creatine metabolism was validated in in vitro and in vivo prostate cancer models and in clinical cases. Upregulated creatine levels were due to increased uptake through the SLC6A8 creatine transporter and de novo synthesis, resulting in enhanced cellular basal respiration. Treatment with cyclocreatine (a creatine analogue that potently and specifically blocks the phosphagen system) dramatically reduces creatine and phosphocreatine levels. Blockade of creatine biosynthesis by cyclocreatine leads to cellular accumulation of S-adenosyl methionine (SAM), an intermediary of creatine biosynthesis, and suppresses prostate cancer growth in vitro. Furthermore, cyclocreatine treatment impairs cancer progression in our GEMM and in a xenograft liver metastasis model. Hence, by targeting the phosphagen system, cyclocreatine results in anti-tumourigenic effects from both SAM accumulation and suppressed phosphagen system.

scholarly journals A balancing act: PHLPP2 fine tunes AKT activity and MYC stability in prostate cancer

2019 ◽  
Vol 218 (6) ◽  
pp. 1771-1772 ◽  
Author(s):  
Roxanne Toivanen ◽  
Luc Furic
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Disease Progression ◽  
Prostate Tumor ◽  
Pten Loss ◽  
Akt Activation ◽  
Cell Biol

PTEN loss stimulates prostate tumor progression by sustaining AKT activation. Nowak et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201902048) surprisingly show that the AKT-suppressing phosphatase PHLPP2 promotes disease progression in the context of dual PTEN and p53 loss by increasing MYC stability.

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