The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?

•αKG is at the center of metabolic reactions essential for cells.•αKG regulates enzymes involved in hypoxic adaptation and epigenetic modifications.•Elevated intracellular levels of αKG impinge on tumor progression.•Increase of αKG levels may represent a possible anti-cancer strategy. The thriving field that constitutes cancer metabolism has unveiled some groundbreaking facts over the past two decades, at the heart of which is the TCA cycle and its intermediates. As such and besides its metabolic role, α-ketoglutarate was shown to withstand a wide range of physiological reactions from protection against oxidative stress, collagen and bone maintenance to development and immunity. Most importantly, it constitutes the rate-limiting substrate of 2-oxoglutarate-dependent dioxygenases family enzymes, which are involved in hypoxia sensing and in the shaping of cellular epigenetic landscape, two major drivers of oncogenic transformation. Based on literature reports, we hereby review the benefits of this metabolite as a possible novel adjuvant therapeutic opportunity to target tumor progression. This article is part of the special issue “Mitochondrial metabolic alterations in cancer cells and related therapeutic targets”.