Alterations of Global Histone H3K9 and H3K27 Methylation Levels in Bladder Cancer

Ellinger, Jörg; Bachmann, Anne; Göke, Friederike; Behbahani, Turang E; Baumann, Claudia; Heukamp, Lukas C.; Rogenhofer, Sebastian; Müller, Stefan

doi:10.1159/000355467

Cited by 44 publications

(38 citation statements)

References 31 publications

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“…In bladder cancer, there are reduced levels of global histone modifications compared with normal urothelium. Histone methylation levels decrease with disease severity and are correlated with advanced pathologic stages in NMIBC and MIBC in a large cohort of clinical samples (23,24). Altered histone modifications are also evident in bladder cancer cell lines, and EZH2, a histone methyl transferase, is found to be frequently overexpressed in high-grade aggressive tumors and associated with transcriptional silencing of tumor suppressor gene E-cadherin (25,26).…”

Section: Introductionmentioning

confidence: 99%

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Sooraj

Cain

et al. 2016

Molecular Cancer Therapeutics

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Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression and correlates with poor survival. We investigated the utility of measuring ATF3 expression as a marker of response to the HDACi pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated the expression of ATF3, correlating with significant alteration in proliferative, migratory, and anchoragedependent growth capacities. Pracinostat also induced growth arrest at the G 0 -G 1 cell-cycle phase, coincident with the activation of tumor suppressor genes. In mouse xenograft bladder cancer models, pracinostat treatment significantly reduced tumor volumes compared with controls, accompanied by reexpression of ATF3 in nonproliferating cells from early to late stage of therapy and in parallel induced antiangiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus, reactivation of ATF3 is an important factor in determining sensitivity to pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer.

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Section: Introductionmentioning

confidence: 99%

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Sooraj

Cain

et al. 2016

Molecular Cancer Therapeutics

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“…Changes in H3K9 methylation levels and distributions are seen in aging ) and cancer (Sulli et al 2012;Ellinger et al 2014). Moreover, H3K9me2-rich genomic regions are highly correlated with increased mutation load in a variety of cancer types (Schuster-Bockler and Lehner 2012), suggesting that heterochromatin regions are more susceptible to DNA damage and improper repair.…”

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confidence: 99%

A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin

et al. 2016

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Repair of DNA double-strand breaks (DSBs) must be properly orchestrated in diverse chromatin regions to maintain genome stability. The choice between two main DSB repair pathways, nonhomologous end-joining (NHEJ) and homologous recombination (HR), is regulated by the cell cycle as well as chromatin context. Pericentromeric heterochromatin forms a distinct nuclear domain that is enriched for repetitive DNA sequences that pose significant challenges for genome stability. Heterochromatic DSBs display specialized temporal and spatial dynamics that differ from euchromatic DSBs. Although HR is thought to be the main pathway used to repair heterochromatic DSBs, direct tests of this hypothesis are lacking. Here, we developed an in vivo single DSB system for both heterochromatic and euchromatic loci in Drosophila melanogaster. Live imaging of single DSBs in larval imaginal discs recapitulates the spatio-temporal dynamics observed for irradiation (IR)-induced breaks in cell culture. Importantly, live imaging and sequence analysis of repair products reveal that DSBs in euchromatin and heterochromatin are repaired with similar kinetics, employ both NHEJ and HR, and can use homologous chromosomes as an HR template. This direct analysis reveals important insights into heterochromatin DSB repair in animal tissues and provides a foundation for further explorations of repair mechanisms in different chromatin domains.

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“…Consequently, loss of H4K20me3 was expected to be associated with a worse prognosis for the patient, which has indeed been shown in literature [9]. Finally, for H3K9me3, literature shows conflicting results with respect to patient survival and prognosis [6-8,27], depending on the type of cancer. Histone modification H3K9me3 is associated with silencing of gene transcription [26], and can hence be involved in aberrant silencing of tumor suppressor genes (i.e.…”

Section: Discussionmentioning

confidence: 90%

“…For example, expression of H3K4me3 was shown to have prognostic value in hepatocellular carcinoma [4] and renal cell carcinoma [5]. Cancer-associated upregulation of H3K9me3 was prognostic in acute myeloid leukemia [6], salivary carcinoma [7] and bladder cancer [8]. Expression of H4K20me3 was shown to be correlated to tumor progression and prognosis in non-small cell lung cancer [9].…”

Section: Introductionmentioning

confidence: 99%

Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer

et al. 2014

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Background: Post-translational modification of histone tails by methylation plays an important role in tumorigenesis. In this study, we investigated the nuclear expression of H3K4me3, H3K9me3 and H4K20me3 in early-stage colon cancer in relation to clinical outcome. Methods: Tumor tissue cores of 254 TNM stage I-III colorectal cancer patients were immunohistochemically stained for H3K4me3, H3K9me3 and H4K20me3 and scored using the semi-automated Ariol system. Cox proportional hazard trend analyses were performed to assess the prognostic value of the combined markers with respect to patient survival and tumor recurrence.

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Alterations of Global Histone H3K9 and H3K27 Methylation Levels in Bladder Cancer

Cited by 44 publications

References 31 publications

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin

Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer

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