Targeting epigenetic regulators to overcome drug resistance in cancers

Abstract

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.

Fig. 1

Common drug resistance mechanisms. There are seven main reasons that can lead to cancer drug resistance, including overexpressed ABC transporters, CSCs, autophagy, apoptosis, gene mutations, EMT, and epigenetic regulation

Fig. 2

Epigenetic regulation mechanisms of drug resistance. Non-coding RNAs, DNA methylation, and histone modifications including histone acetylation and methylation play important roles in tumor resistance. DNA methylation is maintained by DNA methyltransferases and DNA demethylases, histone acetylation is regulated by histone acetyltransferases and histone deacetylases, and histone methylation is maintained by histone demethylases and histone methyltransferases

Fig. 3

The roles of different epigenetic modifications in tumor resistance. DNA methylation is co-regulated by DNA methyltransferases and DNA demethylases, mainly influencing apoptosis, stemness, EMT, and cell proliferation through Notch and Wnt/β-catenin signaling pathways to modulate drug resistance. Non-coding RNAs mainly include four small nucleotides and two large nucleotides, which promote or inhibit tumor resistance. Similarly, histone methylation and acetylation are histone modifications. They keep gene expressions in balance through histone demethylases and methyltransferases, histone acetyltransferases and histone deacetylases, respectively, and function as a double-edged sword in cancer resistance

Fig. 4

Regulation of histone demethylases in tumor resistance. Histone demethylases can contribute to the development of drug resistance by regulating gene transcription, promoting autophagy, reducing apoptosis, affecting cellular metabolic processes, and promoting epithelial-mesenchymal transition. Conversely, targeting histone demethylases by inhibitors or small interfering RNAs can reverse drug resistance

Fig. 5

Classification of histone demethylases and their demethylation sites. There are three families of histone lysine demethylases (shown in different color): lysine-specific demethylase (LSD) family, JMJD family consisting of six families with 21 jmjC domain-containing proteins, and histone arginine demethylases. And different demethylases can demethylate different methylation sites of histones

Fig. 6

Structure domain of LSD family and catalytic mechanism. a Structure domain difference between LSD1 and LSD2. b Structure of histone and the demethylase catalytic process, every two molecules of histone H2A, H2B, H3, and H4 constitute a core protein octamer, and then about 146 bp of DNA is bound around the octamer to form a nucleosome, demethylases can function by removing methyl groups from histones

Fig. 7

Representative inhibitors against histone demethylases in clinical trials

Fig. 8

The roles of lysine-specific demethylase (LSD) family on drug resistance. LSD1 can maintain the function of stem cells by activating NF-κB and Wnt/β-catenin signaling pathway, promote EMT and interact with long-chain non-encoding RNA, thus promoting drug resistance. LSD2 can enhance stem cell characteristics, induce cell apoptosis, and regulate other enzyme expressions to promote drug resistance

Fig. 9

The roles of KDM2 and KDM3 families on drug resistance. KDM2A can promote cell stemness by upregulating the expression of stemness markers Sox2 and Oct4. KDM2B can enhance drug resistance by increasing stem cells and apoptosis at the same time. In addition, KDM3A is able to decrease p53 expression at the transcriptional level and KDM3C can inhibit EMT through the ERK/MAPK signal pathway

Fig. 10

The role of KDM4 family in drug resistance. Small-molecule inhibitors NSC636819 and JIB-04 inhibit KDM4A activity and increase cell sensitivity by affecting CCDC8 expression and apoptosis. Under hypoxia, KDM4B can induce autophagy and increase metabolism through activating the Wnt/β-catenin pathway and transcribing C-Myc respectively. At the same time, KDM4C is able to promote cancer progress by influencing cell cycle and transcription of CDC6, and KDM4D can increase the CSC property through the Wnt/β-catenin and Notch signaling pathways

Fig. 11

The roles of KDM5-7 on drug resistance. In KDM5 family, KDM5A can promote PI3K/AKT/mTOR pathway through ErbB and induce EMT in combination with KDM5D inhibition, thereby leading to drug resistance. However, KDM5C exerts opposite effects by regulating PTEN and p53, PBIT can inhibit the demethylase activity of KDM5B, which in turn affects the MAPK pathway and cell stemness. Besides, KDM6A and KDM6B can enhance drug resistance by promoting cell stemness and regulating the cell cycle, respectively. Importantly, PHF8 can also upregulate the expression of IL6 and FOXA2 to promote drug resistance

Fig. 12

The opposite roles of histone arginine demethylase PAD4 in drug resistance. PAD4 can not only inhibit the production of drug resistance through regulating EMT and apoptosis, but also promote autophagy and enhance drug resistance