Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan

Meisenberg, Cornelia; Ashour, Mohamed E.; El-Shafie, Lamia; Liao, Chunyan; Hodgson, Adam; Pilborough, Alice; Khurram, Syed Ali; Downs, Jessica A.; Ward, Simon E.; El‐Khamisy, Sherif F.

doi:10.1093/nar/gkw1026

Cited by 43 publications

(45 citation statements)

References 63 publications

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“…Some clinical studies showed that the anti-tumor effects of irinotecan are due to the cytotoxic activity of SN-38. 21,22 Studies also showed that treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer PFS and longer overall survival, as compared with treatment with fluorouracil and leucovorin. 23 In some multicenter randomized trials, the response rate and overall survival were significantly higher in patients in the irinotecan group than in those in the no-irinotecan group; time to progression was also significantly longer in the irinotecan group than in the no-irinotecan one.…”

Section: Discussionmentioning

confidence: 99%

Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer

Chen

Huang

et al. 2018

Cancer Biology & Therapy

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Topoisomerase 1 (TOPO-1) and carboxylesterase 2 (CES-2) are found to play crucial roles in the pathogenesis of various cancers. The prognostic role of TOPO-1 and CES-2 in patients with metastatic colorectal cancer (mCRC) who underwent irinotecan chemotherapy was largely unknown. In the current study, we assessed the expression of TOPO-1 and CES-2 in mCRC and analyzed its potential relevance to irinotecan based therapy. A total of 98 patients with mCRC were included in this study. The expression of TOPO-1 and CES-2 in mCRC tissues was evaluated by immunohistochemistry. For TOPO-1, 46 patients showed high expression and 52 patients showed low expression. For CES-2, 53 patients showed high expression and 45 patients showed low expression. The correlation between TOPO-1 or CES-2 expression and clinicopathological characteristics of mCRC patients was analyzed. Neither TOPO-1 nor CES-2 had significant correlation with age, gender, tumor site, tumor grade and metastatic sites in mCRC patients. However, high expression of CES-2 but not TOP-1 was positively correlated with better curative effect. Kaplan-Meier and log-rank test were applied to assess the correlation between progression-free survival (PFS)/overall survival (OS) and TOPO-1 or CES-2 expression in mCRC patients. High expression of TOPO-1 and CES-2 are correlated with longer PFS and OS. In summary, our findings suggest that TOPO-1 and CES-2 may play important roles irinotecan sensitivity in mCRC patients. Evaluation of expression of TOPO-1 and CES-2 may provide preliminary clinical evidence for the management of irinotecan-based therapy in mCRC patients.

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Section: Discussionmentioning

confidence: 99%

Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer

Chen

Huang

et al. 2018

Cancer Biology & Therapy

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“…It has been reported that knock down of class I HDACs in APL cells induced growth arrest and apoptosis [7,12]. Deregulation of histone acetylation has been found in many neoplasms, particularly in leukemia [17].…”

Section: Discussionmentioning

confidence: 99%

“…Loss of acetylation on speci c lysine residues of H3 and H4 is one of the key factors thought to be involved in the progression of carcinogenesis. Moreover, the loss of H4K16 acetylation has been shown to in uence the tumor progression and sensitivity to chemotherapy [11,12]. So, in order to combat these cancers it is important to devise new strategies, one such way is by modulating acetylations levels of histones.…”

Section: Introductionmentioning

confidence: 99%

Selective Targeting of Class1 Histone Deacetylase (HDAC) Isoforms by a Novel Inhibitor SBAK-GHA Potently Resist Leukemogenesis

Bhat¹,

Dar²,

Ahmad³

et al. 2020

Preprint

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Background: Acute promyelocytic leukemia (APL) and acute lymphoblastic leukaemia (ALL) are often presented with loss of H4K16 monoacetylation (ac) and H4K20 trimethylation (3Me) due to increased activity of Class I HDAC’s. In the current study we explored the efficacy and mechanistic basis of a novel Class I HDAC inhibitor SBAK-GHA across different leukemic cell lines and characterised the distinct acetylation pattern on histone H3 and H4.Methods: We initially performed general and class specific HDAC enzyme activity assays to establish the effect of our lead molecule SBAK-GHA. Following, we have probed various acetylation sites to understand a thorough acetylation profile of various leukemic cell lines by immunoblotting. Next, to understand the effect of various Class 1 HDAC isoforms on acetylation levels of hallmark proteins in leukaemia; lentiviral knockdown approach was carried out. In addition, cell cycle analysis was also done to distinguish the pattern of cell cycle phase arrest, followed by Chip-qPCR studies of various cyclins and their relationship with cell cycle arrest. Finally, an in vivo study was performed to confirm the anti-leukemic activity of SBAK-GHA by using specific leukaemia models.Results: SBAK-GHA showed class I HDAC inhibitor activity specifically targeting HDAC 2. SBAK-GHA treatment upregulates H4K16 ac and H4K20 me3 in variety of leukemic cell lines. Similar results were found during knock down of HDAC2 in leukemic cell lines. Moreover, we also observed a coherence of events like cell cycle arrest across different cell types of leukemias and modulation in the levels of acetylation across different cyclin promoters. Further on, studies in various in vivo cancer models demonstrated SBAK-GHA to be highly selective towards lymphocytic leukaemia.Conclusion: Our data provided a basic overview of relationship between different class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia. Our study here presented multiple evidences regarding SBAK-GHA as a novel HDAC2 inhibitor. SBAK-GHA resist leukemogenesis mainly by inducing the repressed H4K16 ac and H4K20 me3. Further, the results in present study had established a relationship between class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia.

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“…47–49 Perturbed histone acetylation stimulates faster access of repair enzymes to the damaged sites and subsequently a higher resistance. 50…”

Section: Discussionmentioning

confidence: 99%

Tyrosyl-DNA phosphodiesterase 1 and topoisomerase I activities as predictive indicators for Glioblastoma susceptibility to genotoxic agents

Wang

Rodriguez-Silva

Rocha

et al. 2019

Preprint

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34Background. Glioblastoma (GBM) patients have an estimated survival of ~15 months with 35 treatment, and the standard of care only modestly enhances patient survival. Identifying 36 biomarkers representing vulnerabilities may allow for selection of efficacious chemotherapy 37 options to address personalized variations in GBM tumors. Irinotecan, currently in clinical trials 38 for GBM, targets topoisomerase I (TOP1) by forming a ternary DNA-TOP1 cleavage complex 39 (TOP1cc) inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair 40 enzyme that may reduce the effectiveness of irinotecan. 41 42 3 Methods. We treated GBM cell lines with increasing concentrations of irinotecan and compared 43 the IC50 values. TOP1 and TDP1 protein levels from each cell type as well as GBM patient tumors 44 were determined by Western blot analysis, while activity levels were ascertained by specific 45 enzymatic assays. Cellular TDP1 was elevated by ectopic expression of wild-type or mutant TDP1. 46 47 Results. After comparing cellular susceptibility to TDP1 and TOP1 concentrations and activities, 48we found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation 49 coefficient R = 0.92) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 50 activity ratio by ectopic expression of wild-type TDP1 increased in irinotecan IC50, while 51 expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. 52 53 Conclusions. TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability 54 to irinotecan, allowing for selection of individual patients for irinotecan treatment based on risk-55 benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to 56 improve GBM patient responsiveness to genotoxic chemotherapies. 57 58 Keywords: glioblastoma, DNA repair, TOP1, TDP1, irinotecan 59 60 Key Points 61 1. TDP1/TOP1 activity ratio correlates with irinotecan sensitivity in GBM cell lines. 62

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Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan

Cited by 43 publications

References 63 publications

Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer

Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer

Selective Targeting of Class1 Histone Deacetylase (HDAC) Isoforms by a Novel Inhibitor SBAK-GHA Potently Resist Leukemogenesis

Tyrosyl-DNA phosphodiesterase 1 and topoisomerase I activities as predictive indicators for Glioblastoma susceptibility to genotoxic agents

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