Fiche publication
Date publication
janvier 2022
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr COTTARD Félicie
Tous les auteurs :
Berlin C, Cottard F, Willmann D, Urban S, Tirier SM, Marx L, Rippe K, Schmitt M, Petrocelli V, Greten FR, Fichtner-Feigl S, Kesselring R, Metzger E, Schüle R
Lien Pubmed
Résumé
Colorectal cancer is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis. KMT9α and KMT9β were overexpressed in colorectal cancer and colocalized with H4K12me1 at promoters of target genes involved in the regulation of proliferation. Ablation of KMT9α drastically reduced colorectal tumorigenesis in mice and prevented the growth of murine as well as human patient-derived tumor organoids. Moreover, loss of KMT9α impaired the maintenance and function of colorectal cancer stem/initiating cells and induced apoptosis specifically in this cellular compartment. Together, these data suggest that KMT9 is an important regulator of colorectal carcinogenesis, identifying KMT9 as a promising therapeutic target for the treatment of colorectal cancer. SIGNIFICANCE: The H4K12 methyltransferase KMT9 regulates tumor cell proliferation and stemness in colorectal cancer, indicating that targeting KMT9 could be a useful approach for preventing and treating this disease.
Mots clés
Aged, Aged, 80 and over, Animals, Apoptosis, genetics, Carcinogenesis, genetics, Case-Control Studies, Cell Proliferation, genetics, Colorectal Neoplasms, genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neoplastic Stem Cells, metabolism, Organoids, metabolism, Protein Multimerization, RNA, Messenger, genetics, Site-Specific DNA-Methyltransferase (Adenine-Specific), chemistry
Référence
Cancer Res. 2022 01 15;82(2):210-220
