ZNF831-YTHDF1-DNMT1/3a feedback loop regulates lung carcinogenesis and progression through WNT7B-FZD5-β-catenin signalling axis

Abstract

Zinc finger protein 831 (ZNF831) is a typical transcription factor involved in gene expression regulation. However, its role and mechanism in lung cancer (LC) remain largely unknown. DNA methylation, hydroxymethylation, and RNA m6A modification were measured by MeDIP, hMeDIP, and MeRIP. The survival and prognostic value were identified using Kaplan-Meier and Cox regression analysis. The function effects, target molecules and signalling pathway were determined in cell and animal model. We found that ZNF831 expression was downregulated through DNA methylation during lung carcinogenesis. ZNF831 could improve survival rate and was an independent protective factor for LC patients. ZNF831 overexpression inhibited LC cell growth, invasion and migration. Conversely, ZNF831 knockdown led to opposite phenotype in vitro and in vivo. Mechanistically, ZNF831 inhibited the expression of RNA-binding protein YTHDF1 through transcriptional regulation and protein interaction. Importantly, YTHDF1 also inversely inhibited ZNF831 expression by promoting DNA methyltransferase DNMT1 and DNMT3a to induce DNA hypermethylation. In addition, ZNF831 inhibited tumor growth and progression through YTHDF1 mediated translational regulation of WNT pathway key genes WNT7B and FZD5. These results demonstrated that the feedback loop of ZNF831-YTHDF1-DNMT1/3a regulates cell growth, migration and invasion via WNT7B-FZD5-β-catenin axis, further providing a new idea for targeting epigenetic regulators of LC.