Histone deacetylases and cancer

Barneda-Zahonero, Bruna; Parra, Maribel

doi:10.1016/j.molonc.2012.07.003

Cited by 382 publications

(307 citation statements)

References 119 publications

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“…These findings are consistent with the previous observation that Class I and Class II HDACs are differentially expressed in cancers, and that the Class IIa HDACs exert a dual role in cancer. 38 To test the hypothesis that HDACs inhibit KLF4 expression in lung cancer, we treated the lung cancer cell A549 as well as HEK293T cells with HDAC inhibitors and analyzed the expression of KLF4 and its target genes by RT-PCR and real-time PCR. We found that KLF4 was induced in cells treated with several HDAC inhibitors, including suberoylanilide Figure 5c), which are inhibitors of Class I and IIa HDACs.…”

Section: Resultsmentioning

confidence: 99%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifeninduced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

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Section: Resultsmentioning

confidence: 99%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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“…pH 7.4) for 15 min at room temperature, and washed in PBS (pH 6.0) supplemented with 1 mM MgCl 2 . Cells were incubated with X-gal solution (1 mg/ml X-gal (Inalco, San Luis Obispo, CA, USA), 0.2 M K 3 Fe(CN) 6 , 0.2 M K 4 Fe(CN) 6 3H 2 O) for 4 h at 37°C, and then washed with PBS and incubated with 3.7% formalin (in PBS) for 30 min at room temperature. Images were taken using Olympus microscope (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…4,5 Histone deacetylases (HDACs) recruited to the methylated cytosines can create a closed chromatin state that is less accessible for transcription. 6 Compounds such as 5′aza-2′-deoxycytidine (5′aza) can reverse CpG island hypermethylation by inactivating DNA methyltransferases. 5′aza is often used in combination with HDAC inhibitors such as Trichostatin A (TSA), to induce the re-expression of epigenetically silenced genes.…”

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confidence: 99%

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

et al. 2015

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MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumorsuppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.

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“…Each group is subdivided based on sequence identity and domain organization, with up to seven isoenzymes/class, associated with varying substrate specificities and biological functions. HDAC inhibitors (HDACi) promote cellular apoptosis and/or differentiation and originally were developed as anticancer drugs (11). However, more recent evidence demonstrates that HDACi also have antiinflammatory effects in several animal models of inflammatory diseases (12)(13)(14).…”

mentioning

confidence: 99%

Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1–Independent Mechanism

Stammler

Eigenbrod

Menz

et al. 2015

The Journal of Immunology

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Histone deacetylase (HDAC) inhibitors (HDACi) are clinically approved anticancer drugs that have important immune-modulatory properties. We report the surprising finding that HDACi promote LPS-induced IL-1β processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1β maturation and secretion kinetics differed completely from those observed upon inflammasome activation. Moreover, this pathway of IL-1β secretion was dependent on caspase-8 but was independent of the inflammasome components NACHT, LRR, and PYD domains-containing protein 3, apoptosis-associated speck-like protein containing a carboxyl-terminal caspase-recruitment domain, and caspase-1. Genetic studies excluded HDAC6 and HDAC10 as relevant HDAC targets in this pathway, whereas pharmacological inhibitor studies implicated the involvement of HDAC11. Treatment of mice with HDACi in a dextran sodium sulfate–induced colitis model resulted in a strong increase in intestinal IL-1β, confirming that this pathway is also operative in vivo. Thus, in addition to the conventional inflammasome-dependent IL-1β cleavage pathway, dendritic cells and macrophages are capable of generating, secreting, and processing bioactive IL-1β by a novel, caspase-8–dependent mechanism. Given the widespread interest in the therapeutic targeting of IL-1β, as well as the use of HDACi for anti-inflammatory applications, these findings have substantial clinical implications.

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Histone deacetylases and cancer

Cited by 382 publications

References 119 publications

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1–Independent Mechanism

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