@article{WetzelScholtkaSchumacheretal.2021,
  author    = {Wetzel, Alexandra Nicole and Scholtka, Bettina and Schumacher, Fabian and Rawel, Harshadrai Manilal and Geisend{\"o}rfer, Birte and Kleuser, Burkhard},
  title     = {Epigenetic DNA methylation of EBI3 modulates human interleukin-35 formation via NFkB signaling},
  series = {International journal of molecular sciences},
  volume    = {22},
  journal   = {International journal of molecular sciences},
  number    = {10},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22105329},
  pages     = {21},
  year      = {2021},
  abstract  = {Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNF alpha led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NF kappa B signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESIMS/MS analysis of DAC/TNF alpha-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNF alpha-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.},
  language  = {en}
}
@article{WetzelScholtkaGereckeetal.2020,
  author    = {Wetzel, Alexandra Nicole and Scholtka, Bettina and Gerecke, Christian and Kleuser, Burkhard},
  title     = {Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3},
  series = {Cellular and molecular life sciences},
  volume    = {77},
  journal   = {Cellular and molecular life sciences},
  number    = {23},
  publisher = {Springer International Publishing AG},
  address   = {Cham (ZG)},
  issn      = {1420-682X},
  doi       = {10.1007/s00018-020-03451-9},
  pages     = {5017 -- 5030},
  year      = {2020},
  abstract  = {Ulcerative colitis (UC) is characterized by relapsing-remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNF alpha or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3(-/-)). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3(-/-). In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.},
  language  = {en}
}
@article{GereckeScholtkaLoewensteinetal.2015,
  author    = {Gerecke, Christian and Scholtka, Bettina and Loewenstein, Yvonne and Fait, Isabel and Gottschalk, Uwe and Rogoll, Dorothee and Melcher, Ralph and Kleuser, Burkhard},
  title     = {Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer},
  series = {Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft},
  volume    = {141},
  journal   = {Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft},
  number    = {12},
  publisher = {Springer},
  address   = {New York},
  issn      = {0171-5216},
  doi       = {10.1007/s00432-015-1972-8},
  pages     = {2097 -- 2107},
  year      = {2015},
  abstract  = {Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer. Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9). A high methylation frequency of VIM (55.6 \%) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD). The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.},
  language  = {en}
}
@article{MelcherHartmannZopfetal.2011,
  author    = {Melcher, Ralph and Hartmann, Elena and Zopf, Waltraud and Herterich, Sabine and Wilke, Philipp and Mueller, Ludwig and Rosler, Eduard and Kudlich, Theodor and Al-Taie, Oliver and Rosenwald, Andreas and Katzenberger, Tiemo and Scholtka, Bettina and Seibold, Stefan and Rogoll, Dorothee and Scheppach, Wolfgang and Scheurlen, Michael and Luehrs, Hardi},
  title     = {LOH and copy neutral LOH (cnLOH) act as alternative mechanism in sporadic colorectal cancers with chromosomal and microsatellite instability},
  series = {Carcinogenesis : a comprehensive survey},
  volume    = {32},
  journal   = {Carcinogenesis : a comprehensive survey},
  number    = {4},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0143-3334},
  doi       = {10.1093/carcin/bgr011},
  pages     = {636 -- 642},
  year      = {2011},
  abstract  = {Background and aims. Tumor suppressor genes are often located in frequently deleted chromosomal regions of colorectal cancers (CRCs). In contrast to microsatellite stable (MSS) tumors, only few loss of heterozygosity (LOH) studies were performed in microsatellite instable (MSI) tumors, because MSI carcinomas are generally considered to be chromosomally stable and classical LOH studies are not feasible due to MSI. The single nucleotide polymorphism (SNP) array technique enables LOH studies also in MSI CRC. The aim of our study was to analyse tissue from MSI and MSS CRC for the existence of (frequently) deleted chromosomal regions and tumor suppressor genes located therein. Methods and results. We analyzed tissues from 32 sporadic CRCs and their corresponding normal mucosa (16 MSS and 16 MSI tumors) by means of 50K SNP array analysis. MSS tumors displayed chromosomal instability that resulted in multiple deleted (LOH) and amplified regions and led to the identification of MTUS1 (8p22) as a candidate tumor suppressor gene in this region. Although the MSI tumors were chromosomally stable, we found several copy neutral LOHs (cnLOH) in the MSI tumors; these appear to be instrumental in the inactivation of the tumor suppressor gene hMLH1 and a gene located in chromosomal region 6pter-p22. Discussion. Our results suggest that in addition to classical LOH, cnLOH is an important mutational event in relation to the carcinogenesis of MSS and MSI tumors, causing the inactivation of a tumor suppressor gene without copy number alteration of the respective region; this is crucial for the development of MSI tumors and for some chromosomal regions in MSS tumors.},
  language  = {en}
}
@article{GereckeMascherGottschalketal.2013,
  author    = {Gerecke, Christian and Mascher, Conny and Gottschalk, Uwe and Kleuser, Burkhard and Scholtka, Bettina},
  title     = {Ultrasensitive detection of unknown colon cancer-initiating mutations using the example of the adenomatous polyposis coli gene},
  series = {Cancer prevention research},
  volume    = {6},
  journal   = {Cancer prevention research},
  number    = {9},
  publisher = {American Association for Cancer Research},
  address   = {Philadelphia},
  issn      = {1940-6207},
  doi       = {10.1158/1940-6207.CAPR-13-0145},
  pages     = {898 -- 907},
  year      = {2013},
  abstract  = {Detection of cancer precursors contributes to cancer prevention, for example, in the case of colorectal cancer. To record more patients early, ultrasensitive methods are required for the purpose of noninvasive precursor detection in body fluids. Our aim was to develop a method for enrichment and detection of known as well as unknown driver mutations in the Adenomatous polyposis coli (APC) gene. By coupled wild-type blocking (WTB) PCR and high-resolution melting (HRM), referred to as WTB-HRM, a minimum detection limit of 0.01\% mutant in excess wild-type was achieved according to as little as 1 pg mutated DNA in the assay. The technique was applied to 80 tissue samples from patients with colorectal cancer (n = 17), adenomas (n = 50), serrated lesions (n = 8), and normal mucosa (n = 5). Any kind of known and unknown APC mutations (deletions, insertions, and base exchanges) being situated inside the mutation cluster region was distinguishable from wild-type DNA. Furthermore, by WTB-HRM, nearly twice as many carcinomas and 1.5 times more precursor lesions were identified to be mutated in APC, as compared with direct sequencing. By analyzing 31 associated stool DNA specimens all but one of the APC mutations could be recovered. Transferability of the WTB-HRM method to other genes was proven using the example of KRAS mutation analysis. In summary, WTB-HRM is a new approach for ultrasensitive detection of cancer-initiating mutations. In this sense, it appears especially applicable for noninvasive detection of colon cancer precursors in body fluids with excess wild-type DNA like stool. Cancer Prev Res; 6(9); 898-907. (C) 2013 AACR.},
  language  = {en}
}
@article{GereckeSchneiderScholtka2010,
  author    = {Gerecke, Christian and Schneider, Mandy and Scholtka, Bettina},
  title     = {Vimentin promoter methylation analysis is a suitable complement of a gene mutation marker panel for the detection of preneoplastic and neoplastic colonic lesions},
  issn      = {0378-584X},
  doi       = {10.1159/000290860},
  year      = {2010},
  abstract  = {Abstracts: Strukturen veraendern - Heilung verbessern. 29. Deutscher Krebskongress. Berlin 24.-27. Februar 201},
  language  = {en}
}
@article{KuehnelSteinbergScholtka2004,
  author    = {K{\"u}hnel, Dana and Steinberg, Pablo and Scholtka, Bettina},
  title     = {A human-relevant dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PHIP) can induce precancerous lesions in rat intestine after 6 months of exposure},
  issn      = {0028-1298},
  year      = {2004},
  language  = {en}
}
@article{ScholtkaBrossuleit2010,
  author    = {Scholtka, Bettina and Brossuleit, K.},
  title     = {Procedure for the highly sensitive enrichment and detection of the K-RAS codon 12 mutation in faeces from patients with colorectal cancer precursors},
  issn      = {0378-584X},
  year      = {2010},
  language  = {en}
}