Cellular responses to hypoxia (low oxygen) are governed by oxygen sensitive signaling pathways. Such pathways, in part, are controlled by enzymes with oxygen-dependent catalytic activity, of which the role of prolyl 4-hydroxylases has been widely reviewed. These enzymes inhibit hypoxic response by inducing the oxygen-dependent degradation of hypoxia-inducible factor 1α, the master regulator of the transcriptional hypoxic response. Jumonji C domain-containing lysine demethylases are similar enzymes which share the same oxygen-dependent catalytic mechanism as prolyl 4- hydroxylases. Traditionally, the role of lysine demethylases has been studied in relation to demethylation activity against histone substrates, however, within the past decade an increasing number of nonhistone protein targets have been revealed, some of which have a key role in survival in the hypoxic tumor microenvironment. Within this review, we highlight the involvement of methyllysine in the hypoxic response with a focus on the HIF signaling pathway, the regulation of demethylase activity by oxygen, and provide insights into notable areas of future hypoxic demethylase research.

细胞对缺氧（低氧）的反应受氧敏感的信号通路控制。此类途径部分受具有氧依赖性催化活性的酶控制，其中脯氨酰4-羟基酶的作用已被广泛综述。这些酶通过诱导缺氧诱导因子1α（转录低氧反应的主要调节因子）的氧依赖性降解来抑制低氧反应。含有Jumonji C域的赖氨酸脱甲基酶是类似的酶，与脯氨酰4-羟化酶具有相同的氧依赖性催化机理。传统上，赖氨酸脱甲基酶的作用与针对组蛋白底物的脱甲基活性有关，但在过去十年中，已发现越来越多的非组蛋白靶蛋白被发现，其中一些在缺氧肿瘤微环境中的存活中起关键作用。在这篇综述中，我们重点介绍了甲基赖氨酸在低氧反应中的参与，重点是HIF信号通路，氧气对脱甲基酶活性的调节，并提供了对未来低氧脱甲基酶研究的重要领域的见识。