Hypoxia inducible factor is a dominant regulator of adaptive cellular responses to hypoxia and controls the expression of a large number of genes regulating angiogenesis as well as metabolism, cell survival, apoptosis, and other cellular functions in an oxygen level-dependent manner. When a neoplasm is able to induce angiogenesis, tumor progression occurs more rapidly because of the nutrients provided by the neovasculature. Meningioma is one of the most hypervascular brain tumors, making anti-angiogenic therapy an attractive novel therapy for these tumors. HIF-3 alpha has been conventionally regarded as a dominant-negative regulator of HIF-1 alpha, and although alternative HIF-3 alpha splicing variants are extensively reported, their specific functions have not yet been determined. In this study, we found that the transcription of HIF-3 alpha 4 was silenced by the promoter DNA methylation in meningiomas, and inducible HIF-3 alpha 4 impaired angiogenesis, proliferation, and metabolism/oxidation in hypervascular meningiomas. Thus, HIF-3 alpha 4 could be a potential molecular target in meningiomas. (c) 2013 Elsevier Inc. All rights reserved.