Human CREBBP acetyltransferase is impaired by etoposide quinone, an oxidative and leukemogenic metabolite of the anticancer drug etoposide through modification of redox-sensitive zinc-finger cysteine residues

Zhang, Wenchao; Berthelet, Jérémy; Michail, Christina; Bui, Linh‐Chi; Gou, Panhong; Liu, Rongxing; Duval, Romain; Renault, Justine; Dupret, Jean‐Marie; Guidez, Fabien; Chomienne, Christine; Lima, Fernando

doi:10.1016/j.freeradbiomed.2020.11.027

Cited by 11 publications

(9 citation statements)

References 68 publications

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“…Interestingly, the histone methyltransferases G9a and GLP are inhibited by electrophilic compounds able to eject Zn from Zn-fingers from their catalytic domain (Lenstra et al, 2018). Moreover, quinone containing compounds have been reported to inhibit the histone demethylase KDM4A and the CREBBP/p300 acetyltransferase at least in part through Zn ejection from their catalytic Zn-finger domains (Jayatunga et al, 2015;Zhang et al, 2021). We also found that generation of BQ adducts on cysteine Zn-fingers within SETD2 catalytic domain led to the formation of protein cross-links/oligomers that may contribute to enzyme inactivation (Figure 2 and Figure 4).…”

Section: Discussionmentioning

confidence: 99%

The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3)

et al. 2021

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Section: Discussionmentioning

confidence: 99%

The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3)

et al. 2021

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“…CREBBP gene was functions with the histone modi cation as a transcriptional co-activator. CREBBP mutations were common in hematological malignancies and with the clinical relevance and prognostic value in the relapse of pediatric ALL (32,33). The future studies will enlarge the cohorts and prolonger the follow up time to explore the effect of the above mutated genes on the e cacy and survival of ALL.…”

Section: Discussionmentioning

confidence: 99%

Genomic Heterogeneity Contributed To The Different Survival Between Adult and Pediatric Acute Lymphoblastic Leukemia

Chen¹,

Zheng²,

Hong³

et al. 2021

Preprint

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Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to children. Hence, ALL is still a challenging disease to be cured in adult population. Aberrant genetic alterations have been observed previously in ALL, while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study was attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the relationship between the genomic heterogeneity and prognosis. The results showed the similar common mutation types in two populations but the increased prevalence of genetic alterations in adult ALL. The median number of detected gene mutations was 17 (range: 1–53) per sample in adult ALL and 4.5 (range: 1–19) in pediatric ALL(P<0.001). A significant correlation between the increased number of gene mutations and age was found (R2 = 0.5853, P<0.001). 122 and 53 driver genes were identified in adult and pediatric ALL samples, respectively. The IKZF1, IDH1 and TTN mutations were significantly enriched in adult ALL. The incidence of relapse was 40.0% and 9.6% in the adult and pediatric ALL, respectively(P=0.0003). The overall survival (OS) and relapse free survival (RFS) of adult ALL were poorer than pediatric ALL (P=0.0002, P<0.001, respectively). This genomic landscape enhanced the understanding of the biological differences of ALL between the two populations and provided a clue for novel therapeutic approaches.

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“…The benzene metabolite 1,2,4-benzenetriol can influence DNA methylation and histone acetylation in K562 cells [105] . Recently, etoposide quinone has been shown to inhibit certain enzymes, such as the histone acetyltransferase CREBBPwhich is known to be involved in the leukemogenesis [106] . CREBBP(also known as CBP or KAT6A) regulates both normal and malignant hematopoiesis [107] , and the majority of Crebbp +/− or Crebbp −/− mice develop malignant hematopoietic pathologies indicating that CREBBP acts as a tumor suppressor and plays a crucial role in hematopoiesis [108] , [109] , [110] .…”

Section: Etoposide Metabolites Contribute To Therapy-related Leukemia: Non-top2 Factorsmentioning

confidence: 99%

“…CREBBP(also known as CBP or KAT6A) regulates both normal and malignant hematopoiesis [107] , and the majority of Crebbp +/− or Crebbp −/− mice develop malignant hematopoietic pathologies indicating that CREBBP acts as a tumor suppressor and plays a crucial role in hematopoiesis [108] , [109] , [110] . We recently showed that etoposide quinone can inhibit CREBBP acetyltransferase activity by reacting with cysteine within zinc fingers domains that are key for CREBBP activity [106] .…”

Section: Etoposide Metabolites Contribute To Therapy-related Leukemia: Non-top2 Factorsmentioning

confidence: 99%

“…For example, p300, the homolog of CREBBP, is structurally and functionally similar to CREBBP, notably, on the acetyltransferase catalytic core , including RING andPHD domains. Etoposide quinone covalently binds to CREBBP in the RING and PHD domains [106] . Indeed, p300 has similar RING and PHD domains , It is thus likely that etoposide quinone may also inhibit the acetyltransferase activity of p300.…”

Section: Conclusion and Further Challengementioning

confidence: 99%

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Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play

Zhang

Gou

Dupret

et al. 2021

Translational Oncology

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Etoposide is a semi-synthetic glycoside derivative of podophyllotoxin, also known as VP-16. It is a widely used anticancer medicine in clinics. Unfortunately, high doses or long-term etoposide treatment can induce therapy-related leukemia. The mechanism by which etoposide induces secondary hematopoietic malignancies is still unclear. In this article, we review the potential mechanisms of etoposide induced therapy-related leukemia. Etoposide related leukemogenesis is known to depend on reactive oxidative metabolites of etoposide, notably etoposide quinone, which interacts with cellular proteins such as topoisomerases II (TOP2), CREB-binding protein (CREBBP), and T-Cell Protein Tyrosine Phosphatase (TCPTP). CYP3A4 and CYP3A5 metabolize etoposide to etoposide catechol, which readily oxidizes to etoposide quinone. As a poison of TOP2 enzymes, etoposide and its metabolites induce DNA double-stranded breaks (DSB), and the accumulation of DSB triggers cell apoptosis. If the cell survives, the DSB gives rise to the likelihood of faulty DNA repair events. The gene translocation could occur in mixed-lineage leukemia ( MLL ) gene, which is well-known in leukemogenesis. Recently, studies have revealed that etoposide metabolites, especially etoposide quinone, can covalently bind to cysteines residues of CREBBP and TCPTP enzymes, . This leads to enzyme inhibition and further affects histone acetylation and phosphorylation of the JAK-STAT pathway, thus putatively altering the proliferation and differentiation of hematopoietic stem cells (HSC). In brief, current studies suggest that etoposide and its metabolites contribute to etoposide therapy-related leukemia through TOP2 mediated DSB and impairs specific enzyme activity, such as CREBBP and TCPTP.

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Human CREBBP acetyltransferase is impaired by etoposide quinone, an oxidative and leukemogenic metabolite of the anticancer drug etoposide through modification of redox-sensitive zinc-finger cysteine residues

Cited by 11 publications

References 68 publications

The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3)

The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3)

Genomic Heterogeneity Contributed To The Different Survival Between Adult and Pediatric Acute Lymphoblastic Leukemia

Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play

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