Targeting epigenetic regulators for cancer therapy: modulation of bromodomain proteins, methyltransferases, demethylases, and microRNAs

ABSTRACT

Introduction: Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) were the first epigenetic targets to be successfully addressed for cancer treatment, but more recently additional families of epigenetic modulators have been the subject of intense research. Potent inhibitors have been identified in several instances and have proven to be invaluable tools for studying these proteins in normal physiology and in disease. Some have now progressed to clinical studies in hematological and solid tumors, and encouraging early results have been reported.

Areas covered: This article reviews recent advances regarding the roles of new epigenetic players beyond HDACs and DNMTs in cancer, and discusses the impact of selective chemical probes on unravelling their function. The emerging field of non-coding RNAs (ncRNAs) and ongoing clinical studies with epigenetic drugs and microRNAs (miRNAs) are also addressed.

Expert opinion: The roles of different epigenetic factors in numerous cancers have been unraveled recently, leading to the initiation of clinical studies. With inhibitors of BET bromodomain proteins, the histone methyltransferases EZH2 and DOT1L, and the histone demethylase LSD1 progressing through clinical trials, and the recognition of the importance of ncRNAs as potential biomarkers and therapeutics, this bears the hope that novel epigenetic therapies will be approved soon.

KEYWORDS:

• Epigenetics
• cancer
• BET
• EZH2
• DOT1L
• LSD1
• miRNAs

Article highlights

• Epigenetic alterations are involved in tumor development and progression.

• Targeting epigenetic processes potentially addresses multiple gene expression programs that are essential for cancer cells.

• BET proteins are readers of lysine acetylation marks and control transcription of genes involved in cell proliferation and apoptosis.

• Histone methyltransferases and demethylases are often altered and play important roles in the initiation and growth of cancer.

• Compounds targeting BET proteins, methyltransferases, and demethylases have entered clinical trials for different cancer indications.

• miRNAs are commonly dysregulated in cancer, and first miRNA mimics are being evaluated in the clinic.

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Financial and competing interests disclosure

All of the authors are employees of Bayer Schering Pharma AG. M Ocker and B Haendler are also stock-owners of Bayer Schering Pharma AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.