DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, such as hypermethylated suppressor genes and genomic instability, which increase the malignancy of tumors, worsen the prognosis for patients, and greatly increase the difficulty of cancer therapy. However, the impact of DNMTs on tumors is still controversial, and therapeutic approaches targeting DNMTs are still under exploration. Here, we summarize the biological functions and paradoxes associated with DNMTs and we discuss some emerging strategies for targeting DNMTs in tumors, which may provide novel ideas for cancer therapy.

Epigenetic modifications, such as DNA methylation and histone modification, result in heritable changes in gene expression without changing the DNA sequence. Epigenetic regulatory enzymes such as DNA methyltransferases, histone methyltransferases, and histone deacetylases are involved in epigenetic modification. Studies have shown that the dysregulation caused by changes in the amino acid sequence of these enzymes is closely correlated with tumor onset and progression. In addition, certain amino acid changes in the metabolic enzyme isocitrate dehydrogenase (IDH) are linked to altered epigenetic modifications in tumors. Some small molecule inhibitors targeting these aberrant enzymes have shown promising anti-cancer efficacy in preclinical and clinical trials. For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia. In this review, we summarize the recurrent “hotspot” mutations in these enzymes in various tumors and their role in tumorigenesis. We also describe candidate inhibitors of the mutant enzymes which show potential therapeutic value. In addition, we introduce some previously unreported mutation sites in these enzymes, which may be related to tumor development and provide opportunities for future study.

Background: Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored. Methods: We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance. Results: Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2. Conclusion: Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.

A number of novel anticancer drugs have been developed in recent years. However, the mortality of cancer patients remains high because of the emergence of drug resistance. It was reported that drug resistance might involved in changes in gene expression without changing genotypes, which is similar to epigenetic modification. Some studies indicated that targeting histone methyltransferase can reverse drug resistance. Hence, the use of histone methyltransferase inhibitors or histone demethylase inhibitors opens new therapeutic approaches for cancer treatment. While the relationship between histone methyltransferase and tumor resistance has been determined, there is a lack of updated review on the association between them. In this review, we summarized the mechanisms of histone methyltransferases in cancer drug resistance and the therapeutic strategies of targeting histone methyltransferase to reverse drug resistance.