Targeting histone demethylases as a potential cancer therapy (Review)

Abstract

Post-translational modifications of histones by histone demethylases have an important role in the regulation of gene transcription and are implicated in cancers. Recently, the family of lysine (K)-specific demethylase (KDM) proteins, referring to histone demethylases that dynamically regulate histone methylation, were indicated to be involved in various pathways related to cancer development. To date, numerous studies have been conducted to explore the effects of KDMs on cancer growth, metastasis and drug resistance, and a majority of KDMs have been indicated to be oncogenes in both leukemia and solid tumors. In addition, certain KDM inhibitors have been developed and have become the subject of clinical trials to explore their safety and efficacy in cancer therapy. However, most of them focus on hematopoietic malignancy. This review summarizes the effects of KDMs on tumor growth, drug resistance and the current status of KDM inhibitors in clinical trials. Contents1. Introduction 2. Overview of the role of histone demethylases in cancer 3. Role of histone demethylases in cancer therapy resistance 4. KDM inhibitors in cancer therapy 5. Conclusions and perspectives

The role and prospect of lysine‐specific demethylases in cancer chemoresistance

“…As we know, most KDM proteins are upregulated in various cancers, 35,36 and many effective KDM inhibitors have been synthesized and even tested at the clinical study stage. 234 However, the underlying mechanisms of using KDM inhibitors to overcome chemoresistance deserve additional investigation. Some studies have previously validated the nondemethylase functions of KDMs, 22 indicating that these enzymes are more than just methylation erasers.…”

“…As we know, most KDM proteins are upregulated in various cancers, 35,36 and many effective KDM inhibitors have been synthesized and even tested at the clinical study stage 234 . However, the underlying mechanisms of using KDM inhibitors to overcome chemoresistance deserve additional investigation.…”

Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression

“…Additionally, GSK2879552 is being tested in people with high-risk myelodysplastic syndrome, both independently and in conjunction with the DNA methyltransferase inhibitor azacitidine (NCT02929498). Recent studies indicate that LSD1 may have a role in resistance to trans-retinoic acid; comparable trials are being undertaken in patients with relapsed and/or refractory solid tumors, and non-Hodgkin’s lymphoma in conjunction with tranylcypromine (TCP+ATRA; NCT02261779, NCT02273102) and CC-90011 (NCT02875223) [ 100 , 111 , 112 ]. The first trivalent rhodium-based LSD1 inhibitor was described by Yang et al, and showed selectivity over other related enzymes such as KDM2b, KDM7, and monoamine oxidase [ 113 , 114 ].…”