wnt-c59 and Colorectal-Neoplasms

Since chromatin-modifying enzymes are involved in most processes needing to access the DNA fiber such as transcription, replication or DNA repair, their involvement in the regulation of gene expression in numerous physiopathological contexts is widely studied. Most of these enzymes are essential for cell growth and survival due to their pleiotropic roles and studying their impact in vivo on organ development or tissue physiopathology is challenging. In this chapter, we describe a chemically-mediated method to induce colorectal carcinogenesis that we have used to identify in vivo the role of two chromatin modifying enzymes belonging to the same multimolecular complex, the histone acetyltransferase Tip60 and the histone variant-incorporating ATPase p400.

Topics: Animals; Azoxymethane; Benzeneacetamides; Carcinogenesis; Chromatin; Colon; Colorectal Neoplasms; Dextran Sulfate; DNA Helicases; DNA-Binding Proteins; Histones; Humans; Intestinal Mucosa; Lysine Acetyltransferase 5; Mice; Mice, Transgenic; Neoplasms, Experimental; Pyridines; Trans-Activators; Transcription Factors; Wnt Signaling Pathway

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active β-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment.

Topics: Animals; Antineoplastic Agents; Benzeneacetamides; beta Catenin; Brain Neoplasms; Camptothecin; Celecoxib; Cisplatin; Colorectal Neoplasms; Dacarbazine; DNA Modification Methylases; DNA Repair Enzymes; Doxorubicin; Drug Resistance, Neoplasm; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Glucose-6-Phosphate Isomerase; Heterocyclic Compounds, 3-Ring; Humans; Immunoblotting; Immunohistochemistry; Irinotecan; Medulloblastoma; Mice; Neoplasm Transplantation; Neoplasms; Neuroblastoma; Pyrans; Pyrazines; Pyridines; Real-Time Polymerase Chain Reaction; Sulfones; Temozolomide; Triazoles; Tumor Suppressor Proteins; Vincristine; Wnt Proteins; Wnt Signaling Pathway