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

Xia, Limin; Huang, Wenjie; Bellani, Marina A.; Seidman, Michael M.; Wu, Kaichun; Fan, Daiming; Nie, Yongzhan; Cai, Yi; Zhang, Yang W.; Yu, Li; Li, Huili; Zahnow, Cynthia A.; Xie, Wenbing; Yen, Ray Whay Chiu; Rassool, Feyruz V.; Baylin, Stephen B.

doi:10.1016/j.ccell.2017.04.005

Cited by 155 publications

(159 citation statements)

References 41 publications

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“…We also found that MUC1-C upregulates expression of the ATPdependent CHD4 helicase by an MYC-dependent mechanism. CHD4 functions in nucleosome remodeling and in the repression of TSGs by recruitment of epigenetic effectors, such as DNMTs (11,45). As found for targeting MUC1-C (4), silencing CHD4 reactivates hypermethylated TSGs (45), supporting the potential importance of MUC1-C in integrating induction of DNMT3b and the CHD4 protein in the hypermethylation of TSGs.…”

Section: Discussionmentioning

confidence: 59%

MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells

et al. 2019

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The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) Cterminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal-but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells.Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.

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Section: Discussionmentioning

confidence: 59%

MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells

et al. 2019

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“…CHD4, a chromodomain‐containing protein, catalyzes ATP‐dependent chromatin remodeling as a core component of the nucleosome remodeling and histone deacetylase (NuRD) repressor complex, which is involved in the epigenetic regulation of gene transcription, DNA repair, and cell cycle progression, and is a hallmark of virtually all human cancers . Furthermore, TWIST, a transcriptional regulator, interacts with several components of the NuRD complex, and the TWIST/NuRD complex plays an essential role in EMT and metastasis .…”

Section: Discussionmentioning

confidence: 99%

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer

Fujii

Miyata

Takahashi

et al. 2018

Proteomics Clinical Apps

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“…We previously reported that CHD3 and CHD4 are commonly mutated in a subset of breast cancers . Furthermore, a recent study revealed that CHD4 has an oncogenic role in maintaining epigenetic silencing of tumor suppressor genes in colorectal cancer (Xia et al, 2017). CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer (Colbert et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Genotranscriptomic meta‐analysis of the CHD family chromatin remodelers in human cancers – initial evidence of an oncogenic role for CHD7

et al. 2017

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Chromodomain helicase DNA binding proteins (CHDs) are characterized by N‐terminal tandem chromodomains and a central adenosine triphosphate‐dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10 000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amplified and mutated, whereas CHD3 was the most deleted across the majority of tumor types, including breast cancer. Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis. CHD7 is required to maintain open, accessible chromatin, thus providing fine‐tuning of transcriptional regulation of certain classes of genes. We found that CHD7 expression was positively correlated with a small subset of classical oncogenes, notably NRAS, in breast cancer. Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets, including NRAS, in breast cancer cell lines. Thus, our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer.

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

Cited by 155 publications

References 41 publications

MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells

MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer

Genotranscriptomic meta‐analysis of the CHD family chromatin remodelers in human cancers – initial evidence of an oncogenic role for CHD7

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