Epigenetic regulation of mucin genes in human cancers

Yamada, Norishige; Kitamoto, Sho; Yokoyama, Seiya; Hamada, Tomofumi; Goto, Masamichi; Tsutsumida, Hideaki; Higashi, Michiyo; Yonezawa, Suguru

doi:10.1007/s13148-011-0037-3

Cited by 42 publications

(43 citation statements)

References 126 publications

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“…It has been shown previously that expression of mucin genes such as MUC1 , MUC2 , MUC3 , MUC4, and MUC5AC are regulated by DNA methylation (5mC) of these promoter regions [15–17]. Our results are the first to demonstrate that TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung adenocarcinomas.…”

Section: Discussionsupporting

confidence: 67%

TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer

et al. 2017

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Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.

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Section: Discussionsupporting

confidence: 67%

TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer

et al. 2017

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“…In normal cells including human lung and gastric epithelial cells, macrophages and mouse placenta, MUC1 transcription is under the control of several transcription factors such as NF-κB, STAT3, HIF-1, SP1 and PPAR-γ (21,34,(43)(44)(45). In addition, epigenetic regulation including demethylation of the MUC1 promoter, and histone H3-K9 demethylation and acetylation are involved (46). Furthermore, suppressing micro-RNA-mediated downregulation of MUC1 expression was recently reported (25,36,37).…”

Section: Discussionmentioning

confidence: 98%

A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

Xu¹,

Wells²,

Padilla³

et al. 2014

Carcinogenesis

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Acquired chemoresistance is a major challenge in cancer therapy. While the oncoprotein Mucin-1 (MUC1) performs multiple roles in the development of diverse human tumors, whether MUC1 is involved in acquired chemoresistance has not been determined. Using an acquired chemoresistance lung cancer cell model, we show that MUC1 expression was substantially increased in cells with acquired apoptosis resistance (AR). Knockdown of MUC1 expression effectively increased the sensitivity of these cells to the apoptotic cytotoxicity of anticancer therapeutics, suggesting that MUC1 contributes to acquired chemoresistance. Decreased catalase expression and increased cellular reactive oxygen species (ROS) accumulation were found to be associated with MUC1 overexpression. Scavenging ROS with butylated hydroxyanisole or supplying exogenous catalase dramatically suppressed MUC1 expression through destabilizing MUC1 protein, suggesting that reduced catalase expression mediated ROS accumulation is accounted for MUC1 overexpression. Further, we found that increased miR-551b expression in the AR cells inhibited the expression of catalase and potentiated ROS accumulation and MUC1 expression. Finally, by manipulating MUC1 expression, we found that MUC1 promotes EGFR-mediated activation of the cell survival cascade involving Akt/c-FLIP/COX-2 in order to protect cancer cells from responding to anticancer agents. Thus, our results establish a pathway consisting of miR-551b/catalase/ ROS that results in MUC1 overexpression, and intervention against this pathway could be exploited to overcome acquired chemoresistance.

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“…Thus, it is very important to establish new diagnostic, prognostic and therapeutic biomarkers. It has been shown previously that expression of mucin genes (including MUC1 , MUC2 , MUC3 , MUC4 and MUC5AC ) is regulated by DNA methylation at promoter regions in cancer cell lines [18–20, 35, 36]. In the present study, we analyzed the relationships among the expression of two mucins, MUC1 and MUC4 , their DNA methylation status at promoter regions, and expression of DNA methylation-related enzymes in pancreatic tissue in non-neoplastic and PDAC samples.…”

Section: Discussionmentioning

confidence: 99%

“…MUC1 and MUC4 are often overexpressed in epithelial cancers, and our immunohistochemical studies in the pancreas and/or biomolecular studies have shown the following: (1) aberrant expression of MUC1 and MUC4 are associated with invasive proliferation of tumors and a poor outcome for patients [16, 17]; and (2) the expression of MUC1 / MUC4 mRNA is regulated by epigenetic mechanisms such as DNA methylation in the promoter region [18–20]. …”

Section: Introductionmentioning

confidence: 99%

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas

et al. 2016

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Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

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Epigenetic regulation of mucin genes in human cancers

Cited by 42 publications

References 126 publications

TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer

TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer

A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas

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