Histone modifications across cancers: mechanisms, therapy and clinical translation

Cancer continues to be a major cause of death across the globe, and epigenetic dysregulation, including histone modifications, has been recognized as a major hallmark of cancer development, heterogeneity, and drug resistance. This review seeks to offer an overview of histone modifications in cancer, including the more studied histone modifications such as acetylation and methylation, as well as the less explored histone modifications such as phosphorylation, ubiquitination, and glycosylation. It also examines the role of histone modifications in the dysregulation of the three categories of enzymes: the writers, the erasers, and the readers, in the development of cancer, including solid tumors and hematological malignancies. This review also further explores the complex crosstalk between histone modifications, DNA methylation, non-coding RNA, and metabolic reprogramming, focusing on the complex epigenetic networks that maintain oncogenic states and confer plasticity to cancer. In terms of the development of new therapeutic agents, recent advances in epigenetic drugs such as HDAC inhibitors, EZH2 inhibitors, and BET inhibitors are also reviewed, as are new therapeutic avenues such as PROTACs, dual inhibitors, and natural epigenetic modulators. It also emphasizes the fact that the expression of histone modifying enzymes is a key change underlying oncogenic transcriptional states in all cancers. Some of the new aspects of epigenetics revealed in the review include the context-dependent role of H3K27me3 and H2BK120ub modifications, the therapeutic potential of epigenetic targets such as EZH2 and BRD4, and the therapeutic potential of combining epigenetic therapy with chemotherapy and immunotherapy.