Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA

Kumari, Kanchan; Das, Biswajit; Adhya, Amit Kumar; Chaudhary, Sanjib; Senapati, Shantibhusan; Mishra, Sandip K.

doi:10.1038/s41419-017-0224-z

Cited by 19 publications

(24 citation statements)

References 57 publications

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“…To investigate the clinical relevance of our study, we explored the association of EZH2 in real scenario. In our recent study 32 , we report significant role of EZH2 in nicotine-induced increased breast cancer progression. An enhanced expression of EZH2 was observed in nicotine treated breast cancer cells, xenografts and breast cancer patients with smoking history in comparison to non-smoking samples.…”

Section: Resultsmentioning

confidence: 86%

“…Further, to validate the correlated expression of EZH2 targets and EZH2 in conditions such as nicotine consumption, we performed immunohistochemistry with SUMF1, the target showing most significant association with breast cancer patient survival, in tissue sections of smoking and non-smoking breast tumors. Five pairs of appropriately matched 32 smoking and non-smoking breast cancer samples were stained with SUMF1 antibody (Fig. 10D,i).…”

Section: Resultsmentioning

confidence: 99%

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Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival

Kumari

Das

Adhya

et al. 2019

Sci Rep

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Several pioneering work have established that apart from genetic alterations, epigenetic modifications contribute significantly in tumor progression. Remarkable role of EZH2 in cancer highlights the importance of identifying its targets. Although much emphasis has been placed in recent years in designing drugs and inhibitors targeting EZH2, less effort has been given in exploring its existing targets that will help in understanding the oncogenic role of EZH2 in turn which may provide a more stringent method of targeting EZH2. In the present study, we validated six direct targets of EZH2 that are GPNMB, PMEPA1, CoL5A1, VGLL4, POMT2 and SUMF1 associated with cancer related pathways. Upon EZH2 knockdown, more than two fold increase in the target gene expression was evident. CHIP-qPCR performed in both MCF-7 and MDA-MDA-231 confirmed the in-vivo binding of EZH2 on its identified target. Thirty invasive breast carcinoma cases with their adjacent normal tissues were included in the study. Immunohistochemistry in primary breast tumor tissue array showed tumor dependent expression of EZH2. Array of MERAV expression database revealed the strength of association of EZH2 with its target genes. Real time PCR performed with RNA extracted from breast tumor tissues further authenticated the existing negative correlation between EZH2 and its target genes. Pearson correlation coefficient & statistical significance computed using the matrix provided in the database strengthened the negative correlation between identified target genes and EZH2. KM plotter analysis showed improved relapse-free survival with increased expression of PMEPA1, POMT2, VGLL4 and SUMF1 in breast cancer patients indicating their therapeutic potential. While investigating the relevance of these target genes, different mutations of them were found in breast cancer patients. Seeking the clinical relevance of our study, following our recent publication that reports the role of EZH2 in nicotine-mediated breast cancer development and progression, we observed significant reduced expression of SUMF1 in breast cancer patient samples with smoking history in comparison to never-smoked patient samples.

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival

Kumari

Das

Adhya

et al. 2019

Sci Rep

Self Cite

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“…EZH2 can promote the expression of CCND3, CCNE2, CDK4, and CDK6 genes in nasopharyngeal carcinoma [ 24 ]. EZH2 has been shown to enhance the transactivation of c-MYC and cyclin D1 promoters in breast cancer cell lines [ 25 ]. Ectopic over-expression of EZH2 is associated with the upregulation of β-Catenin, CCND1, and EGFR in human hepatocellular carcinoma [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Coexpression Analysis of the EZH2 Gene Using The Cancer Genome Atlas and Oncomine Databases Identifies Coexpressed Genes Involved in Biological Networks in Breast Cancer, Glioblastoma, and Prostate Cancer

et al. 2020

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Background This study aimed to perform coexpression analysis of the EZH2 gene using The Cancer Genome Atlas (TCGA) and the Oncomine databases to identify coexpressed genes involved in biological networks in breast cancer, glioblastoma, and prostate cancer, with functional analysis of the EZH2 gene in the C4-2 human prostate cancer cell line in vitro . Material/Methods Data from TCGA and Oncomine databases were analyzed to determine the expression of EZH2 and the top five coexpressed genes in breast cancer, glioblastoma, and prostate cancer and the clinical significance the coexpressed genes. Gene Ontology (GO) analysis was performed to predict the functions and pathways of EZH2 using pathway annotation. The role of EZH2 in the C4-2 human prostate cancer cell line was studied in vitro. Results Analysis of 16 micro-arrays identified 185 genes that were coexpressed with EZH2. The top five coexpressed genes were MCM4, KIAA0101, MKI67, RRM2, and CDC25a. Increased expression of these genes and EZH2 were associated with reduced survival. Coexpressed genes were involved in biological networks associated with the cell cycle, mitosis, and DNA damage. The effects of EZH2 on prostate cancer cell was validated in vitro as knockdown of EZH2 resulted in a G2/M cell cycle arrest, increased DNA damage, and reduced colony number. Conclusions Coexpression analysis of EZH2 identified its role in the cell cycle, mitosis, and DNA repair. The molecular mechanisms involved in EZH2 gene expression in the cell response to DNA damage requires further study to determine whether EZH2 is a potential human cancer biomarker.

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“…In the present study, a higher frequency of breast cancer patients with smoking or alcohol habits was observed. Multiple reports have also shown that habit of smoking and alcohol consumption were associated with increased risk for breast cancer as they are more exposed to free radicals leading to oxidative damage to lipids, proteins and DNA that may aid in cancer progression ( Kumari et al, 2018 ; Scheideler & Klein, 2018 ). In contrast, several reports have been inconsistent, wherein no significant association was observed with respect to smoking and alcohol consumption in breast cancer patients ( Byrne, Rockett & Holmes, 2002 ; Allen et al, 2009 ; Gathani et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Association of CYBA gene (-930 A/G and 242 C/T) polymorphisms with oxidative stress in breast cancer: a case-control study

Tupurani

Padala

Puranam

et al. 2018

PeerJ

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BackgroundOxidative stress (OS) is a key characteristic feature in cancer initiation and progression. Among multiple cancers, NADPH oxidase (NOX) dependent free radical production is implicated in oxidative stress. P22phox, a subunit of NADPH oxidase encoded by the CYBA gene has functional polymorphisms associated with various complex diseases. The present study was aimed to examine the importance and association of the functional polymorphisms of CYBA gene (-930 A/G and 242 C/T) with the oxidative stress in breast cancer (BC) development and progression.Materials and MethodsWe have performed a case-control study on 300 breast cancer patients and 300 healthy individuals as controls to examine the role of CYBA gene -930 A/G and 242 C/T single nucleotide polymorphisms (SNPs) using As-PCR and PCR-RFLP assays and its association with OS as measured by plasma MDA levels. Linkage disequilibrium (LD) plots were generated using Haploviewtool and Multifactor dimensionality reduction (MDR) analysis was applied to assess high-order interactions between the SNPs. The Insilco analysis has been performed to predict the effect of SNPs on the gene regulation using online tools.ResultsWe have found that genotype frequencies of CYBA gene -930 A/G and 242C/T polymorphism were significantly different between controls and BC patients (p < 0.05). The haplotype combination -930G/242C and -930G/242T were associated with 1.44 & 1.56 folds increased risk for breast cancer respectively. Further, the MDA levels were higher in the patients carrying -930G/242C and -930G/242T haplotype (p < 0.001). Our results have been substantiated by Insilco analysis.ConclusionResults of the present study suggest that GG genotype of -930 A/G polymorphism, -930G/242C and -930G/242T haplotypes of CYBA gene polymorphisms have shown association with higher MDA levels in breast cancer patients, signify that elevated oxidative stress might aid in increased risk for breast cancer initiation and progression.

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Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA

Cited by 19 publications

References 57 publications

Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival

Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival

Coexpression Analysis of the EZH2 Gene Using The Cancer Genome Atlas and Oncomine Databases Identifies Coexpressed Genes Involved in Biological Networks in Breast Cancer, Glioblastoma, and Prostate Cancer

Association of CYBA gene (-930 A/G and 242 C/T) polymorphisms with oxidative stress in breast cancer: a case-control study

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