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Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression

ABSTRACT: Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression

PROVIDER: PRJNA607845 | ENA |

REPOSITORIES: ENA

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Project description:Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus. Excessive activation of the canonical Wnt/β-catenin pathway contributes to the development of cardiomyopathy in type 1 diabetes mellitus (T1DM). Transcription factor 7-like 2 (TCF7L2) is the main β-catenin partner of the TCF family in adult human hearts. In this study, we investigated the role of Wnt/β-catenin in the development of cardiomyopathy in type 2 diabetes mellitus (T2DM) by using streptozotocin (STZ)/high-fat diet (HFD)-induced diabetic mice and high glucose-stimulated neonatal rat cardiomyocytes (NRCMs) as in-vivo and in-vitro models of T2DM, respectively. Compared with the control mice, the T2DM mice exhibited increased myocardial β-catenin and TCF7L2 expression that was concentrated in the nucleus. Treatment of diabetic mice with the β-catenin/TCF7L2 bipartite inhibitor iCRT14 prevented myocardial remodeling and improved cardiac dysfunction. iCRT14 also prevented high glucose-induced hypertrophy in NRCMs, while the β-catenin stabilizer SKL2001 worsened hypertrophy. Immunoprecipitation experiments confirmed the formation of the β-catenin/TCF7L2 bipartite in the control and T2DM mouse cardiomyocytes. Moreover, carbonic anhydrase 2 (CA2) was upregulated in T2DM cardiomyocytes in vitro and in vivo. TCF7L2 overexpression upregulated CA2, while iCRT14 treatment or TCF7L2 knockdown downregulated CA2. Chromatin immunoprecipitation (ChIP) experiments revealed an increased interaction between β-catenin/TCF7L2 and the transcription initiation region of CA2 in the heart tissue of T2DM mice. CA2 knockdown ameliorated NRCM hypertrophy induced by high glucose and SKL2001. A luciferase reporter assay confirmed that CA2 is directly regulated by the β-catenin/TCF7L2 bipartite. Collectively, these results indicate that the canonical Wnt/β-catenin pathway upregulates CA2 via TCF7L2 to promote cardiomyopathy in T2DM. This research sheds new light on the pathogenesis of DCM and presents new potential therapeutic targets for this disease.

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Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression

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