METTL16 Inhibits Lens Epithelial Cells Function in Diabetic Cataract via m6A-Modified DKK1-Mediated Wnt/β-Catenin...

To explore the role of methyltransferase-like protein 16 (METTL16), an N6-methyladenosine (m6A) methyltransferase, in the development and progression of diabetic cataracts (DCs), as its underlying molecular mechanisms remain unknown.

We evaluated m6A methylation levels in total RNA isolated from DC anterior capsule tissue and high glucose (HG)-induced human lens epithelial cells (HLECs) using m6A quantification and dot blot analysis. The expression levels of METTL16 in the anterior capsule tissue were detected using western blot analysis. Methylated RNA immunoprecipitation (MeRIP), RNA stability assays, and other relevant experiments were performed to investigate the regulatory mechanisms of METTL16 on methylation levels in HLECs. Additionally, cellular functions including proliferation, migration, and cell-cycle progression were assessed.

The expression level of METTL16 and the level of m6A methylation were highly elevated in the DC anterior capsule tissue and HG-induced HLECs. MeRIP analysis revealed that Dickkopf-1 (DKK1) might act as the target of METTL16 via the Wnt/β-catenin pathway. Notably, the expression of DKK1 increased with the increase in METTL16 expression in HG-induced HLECs. Furthermore, DKK1 expression was negatively correlated with the nuclear translocation of β-catenin, thereby regulating cell proliferation, migration, and cell-cycle progression in HLECs. In addition, HG-induced lens opacity contributes to cataract formation, and treatment with the DKK1 inhibitor WAY-262611 effectively prevented the development of this pathological process.

The METTL16-DKK1-Wnt/β-catenin axis inhibits the proliferation, migration, and cell-cycle progression of HG-induced HLECs. These findings provide an epigenetic insight into the pathogenesis of DC.