Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy

Cancer treatment is a significant challenge for the global health system, although various pharmacological and therapeutic discoveries have been made. It has been widely established that cancer is associated with epigenetic modification, which is reversible and becomes an attractive target for drug development. Adding chemical groups to the DNA backbone and modifying histone proteins impart distinct characteristics on chromatin architecture. This process is mediated by various enzymes modifying chromatin structures to achieve the diversity of epigenetic space and the intricacy in gene expression files. After decades of effort, epigenetic modification has represented the hallmarks of different cancer types, and the enzymes involved in this process have provided novel targets for antitumor therapy development. Epigenetic drugs show significant effects on both preclinical and clinical studies in which the target development and research offer a promising direction for cancer therapy. Here, we summarize the different types of epigenetic enzymes which target corresponding protein domains, emphasize DNA methylation, histone modifications, and microRNA-mediated cooperation with epigenetic modification, and highlight recent achievements in developing targets for epigenetic inhibitor therapy. This article reviews current anticancer small-molecule inhibitors targeting epigenetic modified enzymes and displays their performances in different stages of clinical trials. Future studies are further needed to address their off-target effects and cytotoxicity to improve their clinical translation.

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy

Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.

Long noncoding RNA HOXA-AS2 functions as an oncogene by binding to EZH2 and suppressing LATS2 in acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) is the most common hematological malignancy in the world. Long noncoding RNAs (lncRNAs) play an important role in the development of physiology and pathology. Many reports have shown that lncRNA HOXA cluster antisense RNA 2 (HOXA-AS2) is a carcinogen and plays an important role in many tumors, but little is known about its role in AML. The aim of this study was to explore the potential mechanism and role of HOXA-AS2 in AML. HOXA-AS2 was upregulated in AML cell lines and tissues, and the overexpression of HOXA-AS2 is negatively correlated with the survival of patients. Silencing HOXA-AS2 can inhibit the proliferation and induce differentiation of AML cells in vitro and in vivo. Overexpressing HOXA-AS2 showed the opposite result. Moreover, more in-depth mechanism studies showed that carcinogenicity of HOXA-AS2 exerted mainly through binding with the epigenetic inhibitor Enhancer of zeste homolog 2 (EZH2) and then inhibiting the expression of Large Tumor Suppressor 2 (LATS2). Taken together, our findings highlight the important role of HOXA-AS2 in AML, suggesting that HOXA-AS2 may be an effective therapeutic target for patients with AML.