Chfr is linked to tumour metastasis through the downregulation of HDAC1

Oh, Young Mi; Kwon, Young Eun; Kim, Joo Mi; Bae, Sung Jun; Lee, Bo Keun; Yoo, Soon Ji; Chung, Chin Ha; Deshaies, Raymond J.; Seol, Jae Hong

doi:10.1038/ncb1837

Cited by 80 publications

(82 citation statements)

References 24 publications

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“…CHFR downregulates histone deacetylase 1 (HDAC1) through its ectopic expression, leading to the upregulation of p21 CIP1/WAF1 as well as of metastasis suppressors KAI1 and E-cadherin. 24 CHFR also negatively regulates NF-jB and p65. 25 These data might indicate that CHFR functions not only as a cell-cycle checkpoint component but also possibly as a regulator of downstream oncogenic molecules.…”

Section: Discussionmentioning

confidence: 99%

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

Koga

Takeshita

Yano

et al. 2010

Intl Journal of Cancer

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Aberrant promoter methylation of the checkpoint gene with forkhead-associated domain and ring finger (CHFR) gene is frequently detected in human cancer. We previously demonstrated that diminished CHFR expression was significantly correlated with both poor prognosis and heavy smoking in nonsmall cell lung cancer (NSCLC). Conversely, epidermal growth receptor (EGFR) mutation is detected in NSCLC among those who have never smoked or smoked lightly. To address the frequency of CHFR hypermethylation as well as differences in the distributions and clinicopathologic backgrounds against EGFR mutation in NSCLC, we investigated a large group of 208 NSCLC patients, including 165 with adenocarcinoma (ADC), 40 with squamous cell carcinoma and three others. We found that CHFR hypermethylation and EGFR mutation are mutually exclusive and have contrastive clinicopathologic backgrounds in NSCLC. Methylation-specific polymerase chain reaction (MSP) and direct DNA sequencing were performed to detect CHFR hypermethylation and EGFR mutation, respectively. CHFR hypermethylation was found in 29 cases (14%) (16 ADC (8%), 12 SCC (6%) and one adenosquamous carcinoma), while EGFR mutation was detected in 48 (23%) cases, all of which were ADC. CHFR hypermethylation and EGFR mutation were mutually exclusive (p 5 0.004). NSCLC with altered CHFR was significantly correlated with smoking history, poor differentiation, lymphatic invasion, and poor prognosis; this contrasted sharply with EGFR mutation, which had statistically better clinical outcomes. Our results demonstrate that CHFR loss might be critical for the tumorigenesis of NSCLC in patients with a history of smoking and induces tumors of a more malignant phenotype than the EGFR mutation. Thus, CHFR alteration should be considered a therapeutic target against NSCLC in patients with poor prognoses.Lung cancer is a leading cause of cancer mortality worldwide; it accounts for over a million deaths annually and still has a poor prognosis.1 Nonsmall cell lung cancer (NSCLC) is the main form of lung cancer, which has three major histologic types: squamous cell carcinoma (SCC), adenocarcinoma (ADC) and large cell carcinoma (LCC).2 Among these, ADC has become the most common type in Western countries.2 It is widely accepted that NSCLC is the result of a series of molecular changes, including oncogene activation and the loss of tumor suppressor genes. Recently, epidermal growth receptor (EGFR) mutation has been receiving increasing attention for its specific clinical response to the anticancer drug gefitinib.3 EGFR mutations are found in 10-40% of NSCLC and are clinicopathologically characterized by female gender, no smoking history and ADC histology, especially with bronchioloalveolar features. [4][5][6] In addition to these data, patients with EGFR mutation have fairly good survival rates. 3Plenty of knowledge has accumulated about EGFR mutation, but there is still no full understanding of the molecular abnormality that is a counterpart of NSCLC and that is associated with smoking and poor clin...

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Section: Discussionmentioning

confidence: 99%

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

Koga

Takeshita

Yano

et al. 2010

Intl Journal of Cancer

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“…21 The C-terminal portion contains an IAC(E/D)E motif (IACEE in HDAC1 and IACDE in HDAC2) involved in the interaction with the pocket proteins PRb, P107, and P130. 8 HDAC1 has a 2-residue Chfr interaction domain that is essential for the interaction with Chfr, an ubiquitin ligase regulating protein degradation, 22 and a nuclear localization signal at the C terminus. 21 A coiled-coil domain is only found at the C terminus of HDAC2.…”

Section: Structure and Complexes Of Mammalian Hdac1 And Hdac2mentioning

confidence: 99%

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

Schultz

2016

Cell Death Differ

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Oocyte and preimplantation embryo development entail dynamic changes in chromatin structure and gene expression, which are regulated by a number of maternal and zygotic epigenetic factors. Histone deacetylases (HDACs), which tighten chromatin structure, repress transcription and gene expression by removing acetyl groups from histone or non-histone proteins. HDAC1 and HDAC2 are two highly homologous Class I HDACs and display compensatory or specific roles in different cell types or in response to different stimuli and signaling pathways. We summarize here the current knowledge about the functions of HDAC1 and HDAC2 in regulating histone modifications, transcription, DNA methylation, chromosome segregation, and cell cycle during oocyte and preimplantation embryo development. What emerges from these studies is that although HDAC1 and HDAC2 are highly homologous, HDAC2 is more critical than HDAC1 for oocyte development and reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development. In eukaryotes, DNA is organized into a highly ordered nucleoprotein assembly called chromatin, whose fundamental unit is the nucleosome. The nucleosome consists of 146 bp of DNA wrapped around a histone core comprised of two molecules each of histones H2A, H2B, H3 and H4. Histone H1 is bound to linker DNA between nucleosomes. 1,2 Histones are subject to multiple post-translational modifications (PTMs), including acetylation, methylation, ubiquitylation, phosphorylation, and sumoylation. These PTMs determine open and closed chromatin conformations, which, in turn, regulate the differential access and recruitment of transcription factors and other regulatory chromatin-binding proteins to DNA. 3-5 Among these histone modifications, histone acetylation is the most well-studied modification, which occurs at the ε-amino groups of evolutionarily conserved lysine residues located at the N termini. Although all core histones are acetylated in vivo, modifications of histones H3 and H4 are more extensively characterized than those of H2A and H2B. Abbreviations: HDAC, histone deacetylase; HAT, histone acetyl transferase; PTM, post-translational modification; KDAC, lysine deacetylase; TSA, trichostatin A; NAD + , nicotinamide adenine dinucleotide; HAD, HDAC association domain ; GVBD, germinal vesicle breakdown; ChIP-seq, chromatin immunoprecipitation sequencing; TFIID, transcription factor II D; YY1, yin yang 1; Pol II CTD S2, serine 2 within the RNApolymerase II C-terminal domain; H3K4, lysine 4 of histone 3; H3K9, lysine 9 of histone 3; H4K16, lysine 16 of histone 4; SIRT, NAD-dependent deacetylase sirtuin; TBP2, TATA-binding protein 2; DNMT, DNA methyltransferases; RBAP46, retinoblastoma binding protein P46; RNAi, RNA interference; aa, amino acidic; BrUTP, 5-Bromouridine 5′-triphosphate; qRT-PCR, quantitative reverse transcription polymerase chain reaction;

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“…HDAC1 can also be acetylated at the catalytic core domain and the C-terminal region, resulting in dramatic reduction of enzymatic activity (Qiu et al, 2006). Other modifications of HDAC1 include sumoylation and ubiquitylation, which also influence deacetylase activity and protein stability (David et al, 2002,Oh et al, 2009. Class II HDACs can also be phosphorylated.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

DNA Methylation and Histone Deacetylation: Interplay and Combined Therapy in Cancer

Qiu¹,

Shabashvili²,

Li³

et al. 2012

DNA Methylation - From Genomics to Technology

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Chfr is linked to tumour metastasis through the downregulation of HDAC1

Cited by 80 publications

References 24 publications

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

DNA Methylation and Histone Deacetylation: Interplay and Combined Therapy in Cancer

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