Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

Romański, A; Schwarz, K.; Keller, Maren; Wietbrauk, Sarah; Vogel, Anja; Roos, Jessica; Oancea, Claudia; Brill, Boris; Krämer, Oliver H.; Ruthardt, Martin; Bug, Gesine

doi:10.4161/cc.21565

Cited by 23 publications

(24 citation statements)

References 38 publications

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“…They found that HDI treatment of PLZF-RARa-or AML1-ETO-expressing murine leukemic HSCs impaired their self-renewal potential as assayed by serial replating experiments. However, residual colony formation was still observed at later replatings in PLZFRARa-expressing leukemic HSCs treated with vorinostat (37).…”

Section: Waf1mentioning

confidence: 99%

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Petruccelli

Pettersson

Rincón

et al. 2013

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDI) show activity in a broad range of hematologic and solid malignancies, yet the percentage of patients in any given malignancy who experience a meaningful clinical response remains small. In this study, we sought to investigate HDI efficacy in acute myeloid leukemia (AML) cells expressing leukemia-associated fusion proteins (LAFP). HDIs have been shown to induce apoptosis, in part, through accumulation of DNA damage and inhibition of DNA repair. LAFPs have been correlated with a DNA repairdeficient phenotype, which may make them more sensitive to HDI-induced DNA damage. We found that expression of the LAFPs PLZF-RARa, PML-RARa, and RUNX1-ETO (AML1-ETO) increased sensitivity to DNA damage and apoptosis induced by the HDI vorinostat. The increase in apoptosis correlated with an enhanced downregulation of the prosurvival protein BCL2. Vorinostat also induced expression of the cell-cycle regulators p19INK4D and p21 WAF1 and triggered a G 2 -M cell cycle arrest to a greater extent in LAFP-expressing cells. The combination of LAFP and vorinostat further led to a greater downregulation of several base excision repair (BER) enzymes. These BER genes represent biomarker candidates for response to HDI-induced DNA damage. Notably, repair of vorinostat-induced DNA double-strand breaks was found to be impaired in PLZFRARa-expressing cells, suggesting a mechanism by which LAFP expression and HDI treatment cooperate to cause an accumulation of damaged DNA. These data support the continued study of HDI-based treatment regimens in LAFP-positive AMLs.

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Section: Waf1mentioning

confidence: 99%

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Petruccelli

Pettersson

Rincón

et al. 2013

Molecular Cancer Therapeutics

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“…[23][24][25] Then we sought to confirm whether HDACis were capable to repress Bmi1 expression in tongue cancer cells. Two HDACis, TSA and NaB, were used to evaluate their effects on Bmi1 abundance.…”

Section: Hdaci Inhibits Bmi1 Expression In Tongue Cancer Cellsmentioning

confidence: 99%

“…Three canonical HDACi chemical compounds including sodium butyrate (NaB), valproic acid and Trichostatin A (TSA) have capacities to downregulate Bmi1 and derepressed its downstream targets, which are known to be silenced by Bmi1. [23][24][25] Collectively, these results raise the possibility that therapeutic targeting Bmi1 by HDACi may hold potentials as a novel anticancer strategy when used as single agent or in combination with current therapeutic agents.…”

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confidence: 94%

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Wang

Yuan

et al. 2014

Laboratory Investigation

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The polycomb complex protein Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) mediates epigenetic transcriptional silencing by modifying chromatin structure and is critical for stem cell homeostasis and tumorigenesis. Bmi1 is frequently overexpressed in human malignancies and therefore has key diagnostic and prognostic significance, and holds potential as a therapeutic target. Here we sought to characterize the expression patterns and oncogenic roles of Bmi1 in tongue squamous cell carcinoma and to determine the anticancer effects of histone deacetylase inhibitors (HDACis) via Bmi1 inhibition against tongue cancer. Our data revealed that Bmi1 was aberrantly overexpressed in a significant portion of tongue cancers. Elevated Bmi1 is associated with cervical node metastasis, Ki-67 abundance and reduced overall survival, and also serves as an independent prognostic factor for patient outcomes. Short-hairpin RNA-mediated Bmi1 knockdown inhibited cell proliferation and migration, induced cell apoptosis and senescence, reduced colony formation and CD44þ CD133 þ sub-population as well as enhanced cisplatin chemosensitivity, presumably by modulation of p16, p14 and E-cadherin. Moreover, HDACi chemicals Trichostatin A (TSA) and sodium butyrate (NaB) potently inhibited Bmi1 and triggered similar phenotypic changes reminiscent of Bmi1 silencing, although TSA treatment seemed paradoxically to induce some epithelial-mesenchymal transition-like changes in tongue cancer cells. Importantly, NaB-induced antitumor effects were partially attenuated by enforced Bmi1 overexpression in vitro. Genetic Bmi1 silencing and pharmacological inhibition of Bmi1 by NaB treatment significantly impaired tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that Bmi1 serves as a key driver and biomarker with multiple oncogenic functions underlying tongue tumorigenesis. Selected appropriate HDACi compounds like NaB may represent novel therapeutic agents against tongue cancer. Oral cancer is one of the most common cancers worldwide, approximately accounting for 3% of all malignancies in both sexes. It is widely represented as a heterogeneous tumor with aggressive phenotypes and behaviors. The major etiological risks for this malignancy include smoking and alcohol consumption and human papillomavirus infection. 1 The overwhelming majority of oral cancers arises from tongue and is pathologically identified as squamous cell carcinoma (SCC). 2 Despite tremendous advancement in multimodal therapies against oral cancers over the past decades, the overall 5-year survival rate with these devastating diseases, especially those with advanced diseases, has not been markedly improved. 3 Local relapse and cervical lymph node metastasis are recognized as the most prevalent factors affecting patients' survival. Although many oncogenes and tumor suppressors have been identified as key factors underlying oral tumorigenesis, however, no optimal and commonly accepted biomarkers have been established to facilitate disease diagnosis, ...

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“…Beyond this, it will also be interesting to learn to which degree the HDACi/CQ combination strategy can target AML stem cells. Vorinostat was recently shown to reduce the self-renewal properties of AML stem cells, 46 and it remains to be seen whether this effect is potentiated by autophagy inhibition.In conclusion, we showed that inhibition of autophagy can significantly potentiate the apoptotic effect of HDACis in t(8;21) AML1-ETO-positive AML cells. Thus, a combinatorial treatment with autophagy inhibitors and AML1-ETO-targeting drugs, such as VPA or vorinostat, represents an attractive novel therapeutic option that warrants further investigation.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

Torgersen

Engedal

Bøe

et al. 2013

Blood

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Key Points• In AML1-ETO-positive AML cells, HDAC inhibitors induce autophagy, which acts as a prosurvival signal to limit HDAC-induced cell death.• In contrast to the fusion oncoproteins PML-RARA and breakpoint cluster regionabelson, AML1-ETO is not degraded by either basal-or drug-induced autophagy.The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a prosurvival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for promyelocytic leukemia-retinoic acid receptor a and breakpoint cluster region-abelson, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-eight-twenty-one (ETO). We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO but rather has a prosurvival role in AML cells, as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine (CQ) led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Because VPA and CQ are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO-positive leukemia. (Blood. 2013;122(14):2467-2476) IntroductionMacroautophagy, hereafter referred to as autophagy, is a catabolic pathway that is upregulated during times of nutrient limitations or stress to maintain cellular metabolism and organelle integrity. 1Autophagy involves sequestration of cytoplasmic cargo, such as long-lived proteins, damaged organelles, and protein aggregates, into double-membrane vesicles termed autophagosomes, which fuse with lysosomes, leading to degradation of the contents by acidic hydrolases. 1 There is currently a pressing need to understand in which settings autophagy should be inhibited and in which instances autophagy should be activated, to overcome drug resistance and optimize cancer treatment. Recent studies indicate that anticancer treatment may be hampered by the activation of autophagy as a prosurvival mechanism that prevents apoptosis and delays necrosis in the cancer cells. 2,3 Thus, including autophagy inhibitors in cancer therapy could potentially overcome cancer drug resistance. 4,5 However, autophagy has also been suggested to be a mediator of cell death in certain contexts, 6 and it was recently demonstrated that autophagy facilitates basal and therapy-induced degradation of promyelocytic leukemia-retinoic acid receptor a (P...

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Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

Cited by 23 publications

References 38 publications

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

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