The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors.

Autor: Bergin CJ; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Zouggar A; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Mendes da Silva A; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Fenouil T; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.; Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon, France.; Institut de Pathologie Multisite des Hospices Civils de Lyon, Site Est, Groupement Hospitalier Est, Bron, France., Haebe JR; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Masibag AN; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Agrawal G; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Shah MS; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Sandouka T; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada., Tiberi M; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.; University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada.; Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., Auer RC; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.; Department of Surgery, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.; Center for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.; Centre for Infection, Inflammation and Immunity, University of Ottawa, Ottawa, Ontario, Canada., Ardolino M; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.; Center for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.; Centre for Infection, Inflammation and Immunity, University of Ottawa, Ottawa, Ontario, Canada., Benoit YD; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. ybenoit@uottawa.ca.; School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. ybenoit@uottawa.ca.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2024 Mar; Vol. 5 (3), pp. 463-480. Date of Electronic Publication: 2024 Feb 13.
DOI: 10.1038/s43018-024-00727-y
Abstrakt: Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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