CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers

Habano,

doi:10.3892/ijo_00000235

Cited by 42 publications

(33 citation statements)

References 27 publications

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“…It is well established that methylation of cytosine residues of genomic DNA (DNA methylation) of the regulatory region(s) of a gene can lead to silencing or diminished expression of the gene. Of particular interest, the promoter of the CYP1B1 gene exhibits DNA methylation in a portion of colorectal (Habano et al, 2009) and gastric (Kang et al, 2008) cancers. Studies conducted in our laboratory demonstrated the mechanisms through which DNA methylation causes CYP1B1 silencing and also shed light on the mechanisms of gene regulation in mammalian cells in general (Beedanagari et al, 2010a).…”

Section: Role Of Epigenetic Mechanisms In Differential Regulation Of mentioning

confidence: 99%

Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

et al. 2013

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This is a report of a symposium on the potential role of epigenetic mechanisms in the control of drug disposition sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2013 meeting in Boston, MA, April 21, 2013. Epigenetics is a rapidly evolving area, and recent studies have revealed that expression of drug-metabolizing enzymes and transporters is regulated by epigenetic factors, including histone modification, DNA methylation, and noncoding RNAs. The symposium speakers provided an overview of genetic and epigenetic mechanisms underlying variable drug metabolism and drug response, as well as the implications for personalized medicine. Considerable insight into the epigenetic mechanisms in differential regulation of the dioxininducible drug and carcinogen-metabolizing enzymes CYP1A1 and 1B1 was provided. The role of noncoding microRNAs in the control of drug metabolism and disposition through targeting of cytochrome P450 (P450) enzymes and ATP-binding cassette membrane transporters was discussed. In addition, potential effects of xenobiotics on chromatin interactions and epigenomics, as well as the possible role of long noncoding RNAs in regulation of P450s during liver maturation were presented.

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Section: Role Of Epigenetic Mechanisms In Differential Regulation Of mentioning

confidence: 99%

Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

et al. 2013

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“…It is noteworthy that in a portion of colorectal cancers, CpG dinucleotides at the CYP1B1 promoter are fully methylated, whereas CpG dinucleotides at the enhancer are only partially methylated, just as we observed with HepG2 cells (Habano et al, 2009). Our studies are therefore potentially relevant to the development of these cancers and provide insights into the mechanism of CYP1B1 induction and into the regulation of gene expression in mammalian cells in general.…”

Section: Discussionmentioning

confidence: 59%

“…Of considerable importance are the observations that the CYP1B1 promoter exhibits DNA methylation in a portion of colorectal (Habano et al, 2009) and gastric (Kang et al, 2008) cancers. It is noteworthy that in a portion of colorectal cancers, CpG dinucleotides at the CYP1B1 promoter are fully methylated, whereas CpG dinucleotides at the enhancer are only partially methylated, just as we observed with HepG2 cells (Habano et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…DNA methylation suppresses gene expression either directly by interfering with the binding of transcription factors or indirectly by attracting methylated DNA binding factors that recruit histone deacetylases to generate an inactive heterochromatin structure (Singal and Ginder, 1999;Guo et al, 2002). CpG islands have been identified in the enhancer and in the promoter regions of the human CYP1A1 and CYP1B1 genes, and alterations in the DNA methylation status of both the CYP1A1 and CYP1B1 genes occur in various types of cancer (Tokizane et al, 2005;Okino et al, 2006;Kang et al, 2008;Habano et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

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Role of Epigenetic Mechanisms in Differential Regulation of the Dioxin-Inducible HumanCYP1A1andCYP1B1Genes

Beedanagari

Taylor²,

Bui³

et al. 2010

Mol Pharmacol

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The aryl hydrocarbon receptor (AhR) mediates induction of CYP1A1 and CYP1B1 by 2,3,7,8-tetrachlorodibenzo--dioxin (dioxin) via binding to xenobiotic-responsive elements (XREs) in their enhancer regions. CYP1A1 and CYPIB1 were both inducible by dioxin in human MCF-7 cells. However, only CYP1A1 was inducible in human HepG2 cells. Further experiments focused on providing an explanation for this last observation. Dioxin induced the recruitment of AHR and the transcriptional coactivators p300 and p300/cAMP response element-binding protein binding protein-associated factor (PCAF) to the CYP1B1 enhancer in HepG2 cells but failed to induce recruitment of RNA polymerase II (polII) or the TATA binding protein (TBP) and acetylations of histones 3 and 4 or methylation of histone 3 at the promoter. Because p300 was required for dioxin induction of the aforementioned histone modifications at the CYP1B1 promoter and for induction of CYP1B1 transcription (in MCF-7 cells), the recruitments of p300 and AhR, although necessary, are not sufficient for eliciting the above responses to dioxin. Cytosine residues within CpG dinucleotides at the enhancer, including those within the XREs, were partially methylated, whereas those at the promoter were fully methylated. Treatment of HepG2 cells with 5-aza-2Ј-deoxycytidine led to partial demethylation of the promoter, restored polII and TBP binding, and CYP1B1 inducibility. Thus, the deficiency of CYP1B1 induction in HepG2 cells is ascribable to cytosine methylation at the promoter, which prevents recruitment of TBP and polII. It is noteworthy that our data indicate that stable recruitment of p300 and PCAF to the CYP1B1 gene does not require their tethering to the promoter and to the enhancer.

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“…CYP1B1 promoter methylation is downregulated in colorectal cancer (14) and stratifies prognosis in patients with tamoxifen-and non tamoxifen-treated breast cancer (15). The results demonstrated that CYP1B1 promoter methylation changed following treatment with various chemotherapy regimens, indicating complex regulation of CYP1B1 methylation in the bone marrow.…”

Section: Discussionmentioning

confidence: 91%

APC2 and CYP1B1 methylation changes in the bone marrow of acute myeloid leukemia patients during chemotherapy

Xia

Hong

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Aberrant promoter DNA methylation is a major mechanism of leukemogenesis in hematologic malignancies, including acute myeloid leukemia (AML). However, the association between promoter methylation with chemotherapeutic outcomes remains unknown. In the present study, bone marrow samples were collected prior to and following chemotherapy in 30 AML patients. Methylation-specific polymerase chain reaction technology was used to examine the promoter methylation status of adenomatous polyposis col 2 (APC2) and cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1). The results revealed no change in the methylation status of the APC2 promoter in patients following various chemotherapy regimens. However, the methylation status of the CYP1B1 promoter changed in response to 6 different chemotherapy regimens. AML patients of the M3 subtype displayed an induction of the CYP1B1 promoter methylation levels more frequently (57.1%) than patients affected by the other subtypes (M1: 33.3%; M2: 12.5%; M4: 16.7%; M5: 0% and M6: 0%). In addition, a higher frequency of male patients (4/13) exhibited modulation of the CYP1B1 promoter methylation status compared with female patients (3/17). Furthermore, of five AML patients with a poor prognosis, two exhibited changes leading to CYP1B1 hypomethylation and two leading to CYP1B1 hypermethylation. By contrast, three other patients exhibited hypermethylation changes along with remission. This may be explained by the different chemotherapy regimens used to treat these patients or by other unknown factors. The present study revealed that CYP1B1 promoter methylation was induced during chemotherapy, whereas the APC2 promoter remained hemimethylated. Furthermore, the changes in CYP1B1 methylation were dependent on the AML subtypes and the gender of the patients. IntroductionPromoter methylation is important in epigenetics and always leads to transcriptional silencing of tumor suppressor genes in acute myeloid leukemia (AML) (1). Although current chemotherapy regimens result in complete remission in many cases, there is no standard and efficient therapy for refractory AML (2). As aberrant DNA methylation is common in AML, clinical trials using epigenetically-targeted therapies have yielded particularly promising results in the treatment of hematopoietic malignancies (3). Several demethylating agents, including azacytidine and decitabine, have been demonstrated to improve AML prognosis (4).Adenomatous polyposis col 2 (APC2) is a tumor suppressor gene, encoding a protein that controls the stability and nuclear export of β-catenin, which is a Wnt signaling pathway transcriptional coactivator (5). Wnt pathway inhibitors are methylated at a high frequency in AML patients (6). The cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1) gene, which is a candidate target gene in numerous types of cancers, encodes a member of the cytochrome P450 enzyme superfamily. Furthermore, cytochrome P450 enzymes are involved in drug metabolism and the synthesis of cholesterol, steroids and other l...

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CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers

Cited by 42 publications

References 27 publications

Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

Role of Epigenetic Mechanisms in Differential Regulation of the Dioxin-Inducible HumanCYP1A1andCYP1B1Genes

APC2 and CYP1B1 methylation changes in the bone marrow of acute myeloid leukemia patients during chemotherapy

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