Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation

Sperlazza, Justin; Rahmani, Mohamed; Beckta, Jason M.; Aust, Mandy Mayo; Hawkins, Elisa; Wang, Shou Zhen; Sheng, Zhaoxue; Podder, Shreya; Dumur, Catherine I.; Archer, Kellie J.; Grant, Steven; Ginder, Gordon D.

doi:10.1182/blood-2015-03-631606

Cited by 54 publications

(54 citation statements)

References 66 publications

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“…This role may be integral to some oncogenic properties of CHD4 shown by others (Fu et al, 2011; Nio et al, 2015; Sperlazza et al, 2015). We link CHD4 recruitment to DDR processes induced by laser micro-irradiation to trigger SSBs and DSBs, pure DSBs produced by either site-specific restriction endonuclease cutting or CRISPR-CAS technology, and SSBs in the context of BER repair during oxidative damage.…”

Section: Discussionmentioning

confidence: 94%

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

et al. 2017

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SUMMARY An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks. CHD4 knockdown activates silenced TSGs, revealing their role for blunting colorectal cancer cell proliferation, invasion, and metastases. High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival.

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Section: Discussionmentioning

confidence: 94%

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

et al. 2017

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“…In contrast, our data indicate that both CHD4 expression and NuRD complex integrity were maintained despite the complete absence of MBD3 in human primary AML blasts. It is is noteworthy to mention that although conditional inactivation of Mi‐2β ( Chd4 ) caused erythroid leukemia in mice (15), CHD4 depletion selectively sensitizes human AML blasts to genotoxic stress and reduces tumor burden in vivo (3). Together, these results essentially suggest that epigenetic regulation and dependence on specific chromatin regulatory complex are cell type‐specific and context‐dependent phenomena; herein, loss of MBD3 in human myeloid leukemia participates with KDM6A program toward maintenance of oncogenic gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC)–initiated clonal preleukemic disorders of aged individuals that may transform into secondary AML (1, 2). Despite progress in our understanding of AML pathogenesis, the overall 5‐yr survival is ∼20% because of low remission and high incidence of relapse (3, 4). Over the past decade, genome sequencing studies have identified that recurrent somatic mutations in genes encoding chromatin regulators frequently contribute to tumorigenesis (2, 5).…”

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confidence: 99%

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

et al. 2019

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Cancer genome sequencing studies have focused on identifying oncogenic mutations. However, mutational profiling alone may not always help dissect underlying epigenetic dependencies in tumorigenesis. Nucleosome remodeling and deacetylase (NuRD) is an ATP‐dependent chromatin remodeling complex that regulates transcriptional architecture and is involved in cell fate commitment. We demonstrate that loss of MBD3, an important NuRD scaffold, in human primary acute myeloid leukemia (AML) cells associates with leukemic NuRD. Interestingly, CHD4, an intact ATPase subunit of leukemic NuRD, coimmunoprecipitates and participates with H3K27Me3/2‐demethylase KDM6A to induce expression of atypical guanine nucleotide exchange factors, dedicator of cytokinesis (DOCK) 5 and 8 (DOCK5/8), promoting Rae GTPase signaling. Mechanistically, MBD3 deficiency caused loss of histone deacytelase 1 occupancy with a corresponding increase in KDM6A, CBP, and H3K27Ac on DOCK5/8 loci, leading to derepression of gene expression. Importantly, the Cancer Genome Atlas AML cohort reveals that DOCK5/8 levels are correlated with MBD3 and KDM6A, and DOCK5/8 expression is significantly increased in patients who are MBD3 low and KDM6A high with a poor survival. In addition, pharmacological inhibition of DOCK signaling selectively attenuates AML cell survival. Because MBD3 and KDM6A have been implicated in metastasis, our results may suggest a general phenomenon in tumorigenesis. Collectively, these findings provide evidence for MBD3‐deficient NuRD in leukemia pathobiology and inform a novel epistasis between NuRD and KDM6A toward maintenance of oncogenic gene expression in AML.—Biswas, M., Chatterjee, S. S., Boila, L. D., Chakraborty, S., Banerjee, D., Sengupta, A. MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rae GTPase activation in human acute myeloid leukemia. FASEB J. 33, 5268–5286 (2019). http://www.fasebj.org

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“…[30][31][32] Of note, it was recently observed that 1 key regulator of AML cell growth is CHD4, a well-described downstream effector of DNA methylation capable of restricting chromatin accessibility. 33 In relation to hypomethylated sites, it must be considered that the majority of the genome is methylated, and thus the majority of methylated CpGs do not represent a functional regulatory element. Hypomethylated sites could therefore occur in regulatory elements or nonfunctional intra-and intergenic sites.…”

Section: Discussionmentioning

confidence: 99%

Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia

Siggens

Cordeddu

et al. 2017

Blood

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Key Points• DNA demethylation activates new and poised enhancers in AML that cause a leukemic transcriptome.• Only a subset of DNA demethylated enhancers becomes activated. A specific additional activation step is required for enhancer activation.Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. We analyzed 57 AML patients with normal karyotype by using Illumina's 450k array and showed that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, chromatin immunoprecipitation sequencing analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is therefore not sufficient for enhancer activation. Some sites of hypomethylation occur at weak/poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML-specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes, including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation and cause perturbed enhancer activity in cytogenetically normal AML that contributes to a leukemic transcriptome. (Blood. 2017;129(7):e13-e25)

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Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation

Abstract: Key Points CHD4 depletion sensitizes AML cells but not normal CD34+ progenitors to genotoxic agents by relaxing chromatin and impairing DSB repair. CHD4 depletion modulates expression of AML cell genes that regulate tumor formation in vivo and colony formation in vitro.

Cited by 54 publications

References 66 publications

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia

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