Global levels of histone modifications predict prostate cancer recurrence

Ellinger, Jörg; Kahl, Philip; Gathen, Johannes von der; Rogenhofer, Sebastian; Heukamp, Lukas C.; Gütgemann, Ines; Walter, Bernhard; Hofstädter, Ferdinand; Büttner, Reinhard; Müller, Stefan; Bastian, Patrick J.; Ruecker, Alexander von

doi:10.1002/pros.21038

Cited by 187 publications

(120 citation statements)

References 28 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…For example, trimethylation of Histone H3 at the Lysine 4 residue (H3K4me3) is a wellcharacterized histone mark that is enriched at gene transcriptional start sites (TSS) and is associated with transcriptionally active genes (16)(17)(18)(19). Levels of H3K4me3 are globally and locally altered during different developmental stages of cancer, and can serve as a predictor for disease recurrence (20)(21)(22)(23)(24)(25)(26). It was also recently determined that increased H3K4me3 and decreased H3K27me3 is important for activation of genes linked to proliferation and invasion of breast cancer such as matrix metalloproteinases (MMP), ERBB3, Six1, Cyclin A1, Pim-1, and CSPG4 (14).…”

Section: Introductionmentioning

confidence: 99%

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Salz

Deng

Pampo

et al. 2015

Molecular Cancer Research

View full text Add to dashboard Cite

Epigenetic alteration is a hallmark of all cancers. Such alterations lead to modulation of fundamental cancer-related functions, such as proliferation, migration, and invasion. In particular, methylation of Histone H3 Lysine 4 (H3K4), a histone mark generally associated with transcriptional activation, is altered during progression of several human cancers. While the depletion of H3K4 demethylases promotes breast cancer metastasis, the effect of H3K4 methyltransferases on metastasis is not clear. Nevertheless, gene duplications in the human SETD1A (hSETD1A) H3K4 methyltransferase are present in almost half of breast cancers. Herein, expression analysis determined that hSETD1A is upregulated in multiple metastatic human breast cancer cell lines and clinical tumor specimens. Ablation of hSETD1A in breast cancer cells led to a decrease in migration and invasion in vitro and to a decrease in metastasis in nude mice. Furthermore, a group of matrix metalloproteinases (including MMP2, MMP9, MMP12, MMP13, and MMP17) were identified which were downregulated upon depletion of hSETD1A and demonstrated a decrease in H3K4me3 at their proximal promoters based on chromatin immunoprecipitation analysis. These results provide evidence for a functional and mechanistic link among hSETD1A, MMPs, and metastasis in breast cancer, thereby supporting an oncogenic role for hSETD1A in cancer.Implications: This study reveals that hSETD1A controls tumor metastasis by activating MMP expression and provides an epigenetic link among hSETD1A, MMPs, and metastasis of breast cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Salz

Deng

Pampo

et al. 2015

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…At the DNA level, multiple tumor suppressor genes involved in regulation of prostate differentiation, proliferation or metastasis are effectively silenced by promoter methylation; frequently detected already in premalignant lesions (Cooper and Foster, 2009). Furthermore, global chromatin methylation and acetylation studies have revealed histone modification patterns that may be predictive for PrCa recurrence (Ellinger et al, 2010;Bianco-Miotto et al, 2010). For example, increased global levels of Histone H3 lysine 4 dimethylation and H3K18 acetylation are statistically linked to an increased risk of tumor recurrence (Bianco-Miotto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

et al. 2011

View full text Add to dashboard Cite

Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genomewide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD-and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHDfinger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.

show abstract

“…Histone methylation critically determines chromosomal structure and stability, as well as the accessibility of the transcription factor. Global changes in histone methylation have been associated with tumor recurrence and patient survival in prostate cancer, 10,11 non-small-cell lung cancer, 12,13 bladder cancer, 14 squamous-cell carcinoma of the esophagus, 15 and colorectal cancer. 16 The frequently observed changes of histone methylation pattern in human cancers may attribute to the deregulation of upstream histone methyltransferases.…”

mentioning

confidence: 99%

Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b

et al. 2012

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is a major liver malignancy. We previously demonstrated that deregulation of epigenetic regulators is a common event in human HCC. Suppressor of variegation 3-9 homolog 1 (SUV39H1), the prototype of histone methyltransferase, is the major enzyme responsible for histone H3 lysine 9 trimethylation, which, essentially, is involved in heterochromatin formation, chromosome segregation, and mitotic progression. However, the implication of SUV39H1 in hepatocarcinogenesis remains elusive. In this study, we found that SUV39H1 was frequently up-regulated in human HCCs and was significantly associated with increased Ki67 expression (P < 0.001) and the presence of venous invasion (P 5 0.017). To investigate the role of SUV39H1 in HCC development, both gain-and loss-offunction models were established. SUV39H1 overexpression remarkably enhanced HCC cell clonogenicity, whereas knockdown of SUV39H1 substantially suppressed HCC cell proliferation and induced cell senescence. In addition, ectopic expression of SUV39H1 increased the migratory ability of HCC cells, whereas a reduced migration rate was observed in SUV39H1 knockdown cells. The significance of SUV39H1 in HCC was further demonstrated in a nude mice model; SUV39H1 knockdown drastically inhibited in vivo tumorigenicity and abolished pulmonary metastasis of HCC cells. We also identified microRNA-125b (miR-125b) as a posttranscriptional regulator of SUV39H1. Ectopic expression of miR-125b inhibited SUV39H1 3'-untranslated-region-coupled luciferase activity and suppressed endogenous SUV39H1 expression at both messenger RNA and protein levels. We have previously reported frequent down-regulation of miR-125b in HCC. Interestingly, miR-125b level was found to be inversely correlated with SUV39H1 expression (P 5 0.001) in clinical specimens. Our observations suggested that miR-125b down-regulation may account for the aberrant SUV39H1 level in HCC. Conclusion: Our study demonstrated that SUV39H1 up-regulation contributed to HCC development and metastasis. The tumor-suppressive miR-125b served as a negative regulator of SUV39H1. (HEPATOLOGY 2013;57:637-647) H epatocellular carcinoma (HCC) is a prevalent malignancy worldwide and ranks as the third leading cause of cancer-related death. HCC is highly heterogeneous and develops through complex multistep processes that are accompanied by the acquisition of various molecular abnormalities.

show abstract

Global levels of histone modifications predict prostate cancer recurrence

Abstract: Global histone modification levels may help to identify patients with adverse prognosis, and represent a target for the future therapy of PCA.

Cited by 187 publications

References 28 publications

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b

Contact Info

Product

Resources

About