Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.

耐药性是导致癌症复发和预后不良的主要原因。表观遗传调控是一种独立于核苷酸序列变化的基因表达的可遗传变化。作为常见的表观遗传调控机制，DNA甲基化、组蛋白修饰和非编码RNA调控已得到充分研究。越来越多的证据表明，异常的表观遗传调控有助于肿瘤耐药性。因此，靶向表观遗传调控因子是逆转耐药性的有效策略。在这篇综述中，我们主要总结了表观遗传调控在肿瘤耐药中的作用。此外，作为表观遗传修饰的重要因素，组蛋白去甲基化酶介导组蛋白或基因组DNA修饰。在此处，我们全面描述了组蛋白去甲基化酶家族的功能，包括赖氨酸特异性去甲基化酶家族、含有 Jumonji C 结构域的去甲基化酶家族和组蛋白精氨酸去甲基化酶家族，并充分讨论了它们与癌症耐药性相关的调控机制。此外，还描述了治疗策略，包括小分子抑制剂和靶向组蛋白去甲基化酶的小干扰 RNA 以克服耐药性。