Abstract
Ectopic epigenetic mechanisms play important roles in facilitating tumorigenesis. Here, we first demonstrated that ANKDD1A is a functional tumor suppressor gene, especially in the hypoxia microenvironment. ANKDD1A directly interacts with FIH1 and inhibits the transcriptional activity of HIF1α by upregulating FIH1. In addition, ANKDD1A decreases the half-life of HIF1α by upregulating FIH1, decreases glucose uptake and lactate production, inhibits glioblastoma multiforme (GBM) autophagy, and induces apoptosis in GBM cells under hypoxia. Moreover, ANKDD1A is highly frequently methylated in GBM. The tumor-specific methylation of ANKDD1A indicates that it could be used as a potential epigenetic biomarker as well as a possible therapeutic target.
Highlights
The classic hallmark of human cancer genomes is aberrant DNA methylation, including the genome-wide DNA hypomethylation and hypermethylation of CpG islandassociated gene promoters
By MethPrimer analysis, we found that the ANKDD1A promoter contained a CpG island, indicating that hypermethylation may cause the decreased expression of ANKDD1A in glioma
We examined the effect of overexpressing ANKDD1A on hypoxia-inducible factor 1α (HIF1α) ubiquitinated modification, since HIF1α is ubiquitinated by protein von Hippel–Lindau (pVHL) E3 ligase and rapidly degraded by the proteasome under normoxia [24]
Summary
The classic hallmark of human cancer genomes is aberrant DNA methylation, including the genome-wide DNA hypomethylation and hypermethylation of CpG islandassociated gene promoters. The latter leads to the epigenetic silencing of tumor suppressor genes, thereby facilitating the initiation and progression of cancer [1]. Several genes were found to be repressed by promoterassociated CpG island hypermethylation in human GBM and other glioma subtypes [3]. There is currently great interest in characterizing aberrant DNA methylation in human glioma tumors to identify aberrantly functioning molecular pathways and tumor subtypes. The hypermethylation of aberrant tumor suppressor genes is a mechanism about tumor initiation, and a biomarker for tumor diagnosis and prognosis prediction [7, 8]
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