title: Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy.
abstract: A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a β-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.
authors: Department of General and Visceral Surgery, University Medical Center, Göttingen 37075, Germany.
authors: Emil
authors: E
authors: Kendziorra
authors: Kerstin
authors: K
authors: Ahlborn
authors: Melanie
authors: M
authors: Spitzner
authors: Margret
authors: M
authors: Rave-Fränk
authors: Georg
authors: G
authors: Emons
authors: Jochen
authors: J
authors: Gaedcke
authors: Frank
authors: F
authors: Kramer
authors: Hendrik A
authors: HA
authors: Wolff
authors: Heinz
authors: H
authors: Becker
authors: Tim
authors: T
authors: Beissbarth
authors: Reinhard
authors: R
authors: Ebner
authors: B Michael
authors: BM
authors: Ghadimi
authors: Tobias
authors: T
authors: Pukrop
authors: Thomas
authors: T
authors: Ried
authors: Marian
authors: M
authors: Grade
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin