10779/rcsi.10792088.v1 Matthias PA Ebert Matthias PA Ebert Marc Tänzer Marc Tänzer Benjamin Balluff Benjamin Balluff Elke Burgermeister Elke Burgermeister Antje Karen Kretzschmar Antje Karen Kretzschmar David J. Hughes David J. Hughes Reimo Tetzner Reimo Tetzner Catherine Lofton-Day Catherine Lofton-Day Robert Rosenberg Robert Rosenberg Anke C. Reinacher-Schick Anke C. Reinacher-Schick Karsten Schulmann Karsten Schulmann Andrea Tannapfel Andrea Tannapfel Ralf Hofheinz Ralf Hofheinz Christoph Röcken Christoph Röcken Gisela Keller Gisela Keller Rupert Langer Rupert Langer Katja Specht Katja Specht Rainer Porschen Rainer Porschen Jan Stöhlmacher-Williams Jan Stöhlmacher-Williams Tibor Schuster Tibor Schuster Philipp Ströbel Philipp Ströbel Roland M. Schmid Roland M. Schmid TFAP2E-DKK4 and chemoresistance in colorectal cancer. Royal College of Surgeons in Ireland 2019 Aged Antineoplastic Agents Cell Line Tumor Chemoradiotherapy Colorectal Neoplasms DNA DNA Methylation Drug Resistance Neoplasm Epigenesis Genetic Female Gene Expression Gene Expression Regulation Neoplastic Humans Intercellular Signaling Peptides and Proteins Male Microsatellite Instability Middle Aged Mutation Transcription Factor AP-2 Physiology Medical Physics 2019-11-22 17:01:10 Journal contribution https://repository.rcsi.com/articles/journal_contribution/TFAP2E-DKK4_and_chemoresistance_in_colorectal_cancer_/10792088 <p>BACKGROUND: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy.</p> <p>METHODS: We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation.</p> <p>RESULTS: TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P</p> <p>CONCLUSIONS: TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).</p>