Activation of WDHD1 by DNA demethylases promotes MINPP1 transcription and glycolysis in lung adenocarcinoma progression

Metabolic disturbance, particularly of glucose metabolism, is a hallmark of tumors, including non-small cell lung cancer. This study mainly analyzed the role of multiple inositol polyphosphate phosphatase 1 (MINPP1) in regulating glycolysis in lung adenocarcinoma (LUAD) in vitro and in vivo. First, the differential expression of ten-eleven translocation (TET)1/TET3, WD repeat and HMG-box DNA-binding protein 1 (WDHD1), and MINPP1 in tumors and paracancerous tissues of LUAD patients was measured using RT-qPCR and western blot assays. The effects of the WDHD1/MINPP1 axis on the proliferation and glycolysis of LUAD were explored by lentivirus-mediated gene intervention techniques or treatment with the glycolysis inhibitor 2-deoxyglucose (2-DG). The transcriptional regulation of WDHD1 and MINPP1 was probed using ChIP-qPCR, dual-luciferase assay, RT-qPCR, and western blot analyses. The association of TET1/TET3 with WDHD1 promoter demethylation was assessed using qMSP, RT-qPCR, and western blot assay. TET1, TET3, WDHD1, and MINPP1 are all expressed at high levels in tumor tissues of patients with LUAD. TET1/TET3 upregulated WDHD1 expression through demethylation and further mediated MINPP1 transcriptional activation. Administration of the glycolysis inhibitor 2-DG reversed the LUAD glycolytic program, and progression was inhibited by the knockdown of MINPP1. Restoration of MINPP1 also reversed glycolysis and proliferation suppressed by the knockdown of WDHD1. Finally, reactivation of WDHD1 promoted LUAD cell glycolysis and growth, curtailed by knockdown of TET1/TET3. The demethylases TET1/TET3 mediate the demethylation of the WDHD1 promoter to upregulate WDHD1 expression, thereby activating MINPP1 transcription to promote LUAD glycolysis and progression.